TWI579286B - Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of asgpr - Google Patents

Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of asgpr Download PDF

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TWI579286B
TWI579286B TW104115586A TW104115586A TWI579286B TW I579286 B TWI579286 B TW I579286B TW 104115586 A TW104115586 A TW 104115586A TW 104115586 A TW104115586 A TW 104115586A TW I579286 B TWI579286 B TW I579286B
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oct
dioxabicyclo
dihydroxy
methoxy
triazol
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TW201605864A (en
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文森 瑪西堤
班哲明 達瑪
史拜羅斯 黎瑞斯
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輝瑞股份有限公司
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Description

作為去唾液酸糖蛋白受體(ASGPR)導向劑之經取代-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二醇化合物Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compound as a salivary glycoprotein receptor (ASGPR) directing agent

本發明關於經取代-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二醇衍生物類、彼等之晶體結構、醫藥組成物及作為去唾液酸糖蛋白受體(ASGPR)導向劑之用途。The present invention relates to substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol derivatives, their crystal structures, pharmaceutical compositions and as a asialoglycoprotein receptor (ASGPR) use of a directing agent.

對某些分子實體和某些投遞部位，藥物投遞係屬嚴重問題。例如，投遞大分子(諸如反義股或RNAi分子)係困難的，因為該等化合物通常不能穿透細胞膜。再者，具有高負電荷且呈親水性之分子實體可能顯現跨越細胞膜之擴散受限。進一步，對標的投遞部位之選擇性藥物投遞一般被視為挑戰，因為可通透細胞之分子一般不具有選擇性。針對細胞擴散和標的投遞之一種解決方案係與導向劑共軛之藥物。Drug delivery systems are a serious problem for certain molecular entities and certain delivery sites. For example, delivery of macromolecules (such as antisense strands or RNAi molecules) is difficult because such compounds typically do not penetrate cell membranes. Furthermore, molecular entities with high negative charge and hydrophilicity may appear to be diffusion-limited across cell membranes. Further, selective drug delivery to the target delivery site is generally considered a challenge because molecules that are permeable to cells are generally not selective. One solution for cell diffusion and target delivery is a drug that is conjugated to a targeting agent.

導向劑通常能增強藥物屬性，該藥物屬性包括藥物動力學和藥效動力學。導向劑使與彼連接之藥物有效負載能 有效率地被特定細胞攝取且分佈於該特定細胞。業已使用諸如半乳糖、N-乙醯基半乳糖胺及其他半乳糖衍生物類(彼等包括文獻M.G.Finn and V.Mascitti et al.,Journal of the American Chemical Society,134,1978(2012)所描述者)之某些糖作為肝細胞導向劑，因為彼等糖與存在於肝細胞表面上之去唾液酸糖蛋白受體(ASGPR)結合。然而，此等導向劑有時存有某些藥物動力學問題或可能呈現次最佳之藥物動力學輪廓。Directing agents generally enhance drug properties, including pharmacokinetics and pharmacodynamics. The guiding agent enables the drug to be connected to the carrier It is efficiently taken up by specific cells and distributed to that particular cell. For example, galactose, N-ethyl galactosamine and other galactose derivatives have been used (they include the literature MG Finn and V. Mascitti et al., Journal of the American Chemical Society, 134, 1978 (2012) Some of the sugars described are used as hepatocyte directing agents because they bind to the asialoglycoprotein receptor (ASGPR) present on the surface of hepatocytes. However, such targeting agents sometimes have certain pharmacokinetic problems or may present suboptimal pharmacokinetic profiles.

於動物(通常為大鼠、小鼠、狗或非人之靈長類)模式或人體臨床試驗進行靜脈內/口服(IV/PO)藥物動力學(PK)研究以得到藥物如何於體內被吸收、分佈、代謝及消除之資訊。一般而言，藥物於給藥前經甲基纖維素或聚乙二醇(PEG)、糖及水調製。通常經由隱靜脈於達24小時之不同時間點採取血液樣品。取自投藥手臂之血液樣品經集中、離心及血漿收集。該血漿經稀釋以使濃度落入標準曲線之動力學範圍(1至5000ng/ml)。針對所欲之分析物，分析該等血漿樣品。Intravenous/oral (IV/PO) pharmacokinetic (PK) studies in animal (usually rat, mouse, dog or non-human primate) models or human clinical trials to obtain how the drug is absorbed in the body Information on distribution, metabolism, and elimination. In general, the drug is prepared by methylcellulose or polyethylene glycol (PEG), sugar and water prior to administration. Blood samples are usually taken via saphenous vein at different time points up to 24 hours. Blood samples taken from the arm were collected, collected, centrifuged, and collected in plasma. The plasma was diluted to bring the concentration to the kinetic range of the standard curve (1 to 5000 ng/ml). The plasma samples are analyzed for the desired analyte.

因此，仍需要有助於改善藥物動力學輪廓之藥物投遞劑。Therefore, there remains a need for pharmaceutical delivery agents that help to improve the pharmacokinetic profile.

發明簡述Brief description of the invention

本發明之一方面包括式(A)化合物： 其中R1 係-CN、-CH2 -CN、-C≡CH、-CH2 -N3 、-CH2 -NH2 、-CH2 -N(R4 )-S(O)2 -R5 、-CH2 -CO2 H、-CO2 H、-CH2 -OH、-CH2 -SH、-CH=CH-R5 、-CH2 -R5 、-CH2 -S-R5 、-CH2 -N(R4 )-R5 、-CH2 -N(R4 )-C(O)-R5 、-CH2 -N(R4 )-C(O)-O-R5 、-CH2 -N(R4 )-C(O)-N(R4 )-R5 、-CH2 -O-R5 、-CH2 -O-C(O)-R5 、-CH2 -O-C(O)-N(R4 )-R5 、-CH2 -O-C(O)-O-R5 、-CH2 -S(O)-R5 、-CH2 -S(O)2 -R5 、-CH2 -S(O)2 -N(R4 )-R5 、-C(O)-NH2 、-C(O)-O-R5 、-C(O)-N(R4 )-R5 、芳基或雜芳基，其中該芳基或雜芳基可選擇地經R5 取代，或R1 係-Z-X-Y，其中X係連接子或藥物投遞系統，Y係不存在或係選自小分子、胺基酸序列、核酸序列、抗體、寡聚物、聚合物、基因衍生性材料、脂質體、奈米粒子、染料、螢光探針或彼等之組合的配體，且Z係不存在或係-C≡C-、-CH=CH-、-CH2 -、-CH2 -O-、-C(O)-N(R4 )-、-CH2 -S-、-CH2 -S(O)-、-CH2 -S(O)2 -、-CH2 -S(O)2 -N(R4 )-、-C(O)-O-、-CH2 -N(R4 )-、-CH2 -N(R4 )-C(O)-、-CH2 -N(R4 )-S(O)2 -、-CH2 -N(R4 )-C(O)-O-、 -CH2 -N(R4 )-C(O)-N(R4 )-、-CH2 -O-C(O)-、-CH2 -O-C(O)-N(R4 )-、-CH2 -O-C(O)-O-、芳基或雜芳基，其中該芳基或雜芳基可選擇地經R5 取代；R2 係-OH、-N3 、-N(R3 )2 、-N(R3 )-C(O)-R3 、-N(R3 )-C(O)-N(R3 )2 、-N(R3 )-C(O)-OR3 、四唑或***，其中該四唑和***可選擇地經R3 取代，且其中當R1 係-CH2 -OH時，R2 係-N3 、-N(R3 )2 、-N(R3 )-C(O)-R3 、-N(R3 )-C(O)-N(R3 )2 、-N(R3 )-C(O)-OR3 、四唑或***，其中該四唑和***可選擇地經R3 取代；每個R3 各別為-H、-(C1 -C5 )烷基、經鹵素取代之(C1 -C5 )烷基、或(C3 -C6 )環烷基，其中該烷基或環烷基之-CH2 -基可經選自-O-、-S-或-N(R4 )-之雜原子基替代且該烷基之-CH3 基可經選自-N(R4 )2 、-OR4 或-S(R4 )之雜原子基替代，其中該等雜原子基係經至少2個碳原子分隔；每個R4 各別為-H、-(C1 -C20 )烷基或(C3 -C6 )環烷基，其中該烷基或環烷基之1至6個經至少2個碳原子分隔的-CH2 -基可經-O-、-S-或-N(R4 )-替代且該烷基之-CH3 基可經選自-N(R4 )2 、-OR4 或-S(R4 )之雜原子基替代，其中該等雜原子基係經至少2個碳原子分隔；且，其中該烷基和環烷基可經1至6個鹵素原子取代；且每個R5 各別為-H、(C3 -C20 )環烷基或(C1 -C20 )烷基，其中該烷基或環烷基之1至6個經至少2個碳原子分隔的-CH2 -基可經-O-、-S-或-N(R4 )-替代且該烷基之-CH3 基可經選自-N(R4 )2 、-OR4 或-S(R4 )之雜原子基替代，其中該等 雜原子基係經至少2個碳原子分隔；且，其中該烷基和環烷基可經1至6個鹵素原子取代；或彼之醫藥上可接受之鹽。One aspect of the invention includes a compound of formula (A): Wherein R 1 is -CN, -CH 2 -CN, -C≡CH, -CH 2 -N 3 , -CH 2 -NH 2 , -CH 2 -N(R 4 )-S(O) 2 -R 5 , -CH 2 -CO 2 H, -CO 2 H, -CH 2 -OH, -CH 2 -SH, -CH=CH-R 5 , -CH 2 -R 5 , -CH 2 -SR 5 , -CH 2 -N(R 4 )-R 5 , -CH 2 -N(R 4 )-C(O)-R 5 , -CH 2 -N(R 4 )-C(O)-OR 5 , -CH 2 -N(R 4 )-C(O)-N(R 4 )-R 5 , -CH 2 -OR 5 , -CH 2 -OC(O)-R 5 , -CH 2 -OC(O)-N (R 4 )-R 5 , -CH 2 -OC(O)-OR 5 , -CH 2 -S(O)-R 5 , -CH 2 -S(O) 2 -R 5 , -CH 2 -S (O) 2 -N(R 4 )-R 5 , -C(O)-NH 2 , -C(O)-OR 5 , -C(O)-N(R 4 )-R 5 , aryl or a heteroaryl group, wherein the aryl or heteroaryl group is optionally substituted by R 5 , or R 1 is -ZXY, wherein the X line is a linker or a drug delivery system, and the Y line is absent or selected from a small molecule, an amine group Acid sequence, nucleic acid sequence, antibody, oligomer, polymer, gene-derived material, liposome, nanoparticle, dye, fluorescent probe or a combination of these, and the Z system is absent or ligated - C≡C-, -CH=CH-, -CH 2 -, -CH 2 -O-, -C(O)-N(R 4 )-, -CH 2 -S-, -CH 2 -S(O )-, -CH 2 -S(O) 2 -, -CH 2 -S(O) 2 -N(R 4 )-, - C(O)-O-, -CH 2 -N(R 4 )-, -CH 2 -N(R 4 )-C(O)-, -CH 2 -N(R 4 )-S(O) 2 -, -CH 2 -N(R 4 )-C(O)-O-, -CH 2 -N(R 4 )-C(O)-N(R 4 )-, -CH 2 -OC(O) -, -CH 2 -OC(O)-N(R 4 )-, -CH 2 -OC(O)-O-, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally R 5 substituted; R 2 is -OH, -N 3 , -N(R 3 ) 2 , -N(R 3 )-C(O)-R 3 , -N(R 3 )-C(O)-N ( R 3 ) 2 , -N(R 3 )-C(O)-OR 3 , tetrazole or triazole, wherein the tetrazole and triazole are optionally substituted by R 3 , and wherein when R 1 is —CH 2 -OH, R 2 is -N 3 , -N(R 3 ) 2 , -N(R 3 )-C(O)-R 3 , -N(R 3 )-C(O)-N(R 3 2 , -N(R 3 )-C(O)-OR 3 , tetrazole or triazole, wherein the tetrazole and triazole are optionally substituted by R 3 ; each R 3 is -H, - (C 1 -C 5 )alkyl, halo-substituted (C 1 -C 5 )alkyl, or (C 3 -C 6 )cycloalkyl, wherein the alkyl or cycloalkyl-CH 2 - group Substituted by a hetero atom selected from -O-, -S- or -N(R 4 )- and the -CH 3 group of the alkyl group may be selected from -N(R 4 ) 2 , -OR 4 or - S (R 4) group of hetero atom, in which each of these heteroatom-based group with at least 2 carbon atoms separate; each R 4 is Is not -H, - (C 1 -C 20 ) alkyl or (C 3 -C 6) cycloalkyl, wherein the alkyl or cycloalkyl group of 1 to 6, separated by at least 2 carbon atoms, -CH The 2 -yl group may be replaced by -O-, -S- or -N(R 4 )- and the -CH 3 group of the alkyl group may be selected from -N(R 4 ) 2 , -OR 4 or -S(R 4 ) a hetero atomic group substitution wherein the hetero atom groups are separated by at least 2 carbon atoms; and wherein the alkyl group and the cycloalkyl group are substituted by 1 to 6 halogen atoms; and each R 5 is each Is a -H, (C 3 -C 20 )cycloalkyl or (C 1 -C 20 )alkyl group, wherein the alkyl or cycloalkyl group is 1 to 6 -CH 2 - separated by at least 2 carbon atoms The group may be replaced by -O-, -S- or -N(R 4 )- and the -CH 3 group of the alkyl group may be selected from -N(R 4 ) 2 , -OR 4 or -S(R 4 ) a hetero atom radical substitution wherein the hetero atom radicals are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl groups are substituted by 1 to 6 halogen atoms; or a pharmaceutically acceptable salt thereof .

本發明之另一方面包括式(A)化合物： 其中R1 係-CN、-CH2 -CN、-C≡CH、-CH2 -N3 、-CH2 -NH2 、-CH2 -N(R4 )-S(O)2 -R5 、-CH2 -CO2 H、-CO2 H、-CH2 -OH、-CH2 -SH、-CH=CH-R5 、-CH2 -R5 、-CH2 -S-R5 、-CH2 -N(R4 )-R5 、-CH2 -N(R4 )-C(O)-R5 、-CH2 -N(R4 )-C(O)-O-R5 、-CH2 -N(R4 )-C(O)-N(R4 )-R5 、-CH2 -O-R5 、-CH2 -O-C(O)-R5 、-CH2 -O-C(O)-N(R4 )-R5 、-CH2 -O-C(O)-O-R5 、-CH2 -S(O)-R5 、-CH2 -S(O)2 -R5 、-CH2 -S(O)2 -N(R4 )-R5 、-C(O)-NH2 、-C(O)-O-R5 、-C(O)-N(R4 )-R5 、-S(O)3 H、-S(O)2 Cl、-S(O)2 F、芳基或雜芳基，其中該芳基或雜芳基可選擇地經R5 取代，或R1 係-Z-X-Y、-Z-Y、-X-Y、-X、-Y或-Z-X，其中X係連接子或藥物投遞系統，Y係R6 或係選自小分子、胺基酸序列、核酸序列、抗體、寡聚物、聚合物、基因衍生性材料、脂質體、奈米粒子、染料、螢光探針或彼等之 組合的配體，且Z係-C≡C-、-CH=CH-、-CH2 -、-CH2 -O-、-C(O)-N(R4 )-、-CH2 -S-、-CH2 -S(O)-、-CH2 -S(O)2 -、-CH2 -S(O)2 -N(R4 )-、-C(O)-O-、-CH2 -N(R4 )-、-CH2 -N(R4 )-C(O)-、-CH2 -N(R4 )-S(O)2 -、-CH2 -N(R4 )-C(O)-O-、-CH2 -N(R4 )-C(O)-N(R4 )-、-CH2 -O-C(O)-、-CH2 -O-C(O)-N(R4 )-、-CH2 -O-C(O)-O-、芳基或雜芳基，其中該芳基或雜芳基可選擇地經R5 取代；R2 係-OH、-N3 、-N(R3 )2 、-N(R3 )-C(O)-R3 、-N(R3 )-C(O)-N(R3 )2 、-N(R3 )-C(O)-OR3 、-N(R3 )-S(O)2 -R3 、四唑或***，其中該四唑和***可選擇地經R3 取代，且其中當R1 係-CH2 -OH時，R2 係-N3 、-N(R3 )2 、-N(R3 )-C(O)-R3 、-N(R3 )-C(O)-N(R3 )2 、-N(R3 )-C(O)-OR3 、-N(R3 )-S(O)2 -R3 、四唑或***，其中該四唑和***可選擇地經R3 取代；每個R3 各別為-H、-(C1 -C5 )烷基、經鹵素取代之(C1 -C5 )烷基、或(C3 -C6 )環烷基，其中該烷基或環烷基之一或多個-CH2 -基可各別經獨立選自-O-、-S-或-N(R4 )-之雜原子基替代且該烷基之-CH3 基可經選自-N(R4 )2 、-OR4 或-S(R4 )之雜原子基替代，其中該等雜原子基係經至少2個碳原子分隔；每個R4 各別為-H、-(C1 -C20 )烷基或(C3 -C6 )環烷基，其中該烷基或環烷基之1至6個經至少2個碳原子分隔的-CH2 -基可各別經獨立選自-O-、-S-或-N(R4 )-之雜原子替 代且該烷基之-CH3 基可經選自-N(R4 )2 、-OR4 或-S(R4 )之雜原子基替代，其中該等雜原子基係經至少2個碳原子分隔；且，其中該烷基和環烷基可經1至6個鹵素原子取代；每個R5 各別為-H、(C3 -C20 )環烷基或(C1 -C60 )烷基，其中該環烷基之1至6個-CH2 -基或該烷基之1至20個-CH2 -基可各別經獨立選自-O-、-S-或-N(R4 )-之雜原子替代，其中該等雜原子係經至少2個碳原子分隔的，且該烷基之-CH3 基可經選自-N(R4 )2 、-OR4 或-S(R4 )之雜原子基替代，其中該等雜原子基係經至少2個碳原子分隔；且，其中該烷基和環烷基可經鹵素原子取代；且每個R6 各別為H、-C≡CH、-C=CH2 、-CH3 、-N3 、-N(R4 )2 、-OH、-S(O)-(R4 )、-S(O)2 -(R4 )、-C(O)-OH、-S-S-芳基、-S-S-雜芳基、雜環基、芳基或雜芳基，其中每個芳基或雜芳基可選擇地經R5 取代；或彼之醫藥上可接受之鹽。Another aspect of the invention includes a compound of formula (A): Wherein R 1 is -CN, -CH 2 -CN, -C≡CH, -CH 2 -N 3 , -CH 2 -NH 2 , -CH 2 -N(R 4 )-S(O) 2 -R 5 , -CH 2 -CO 2 H, -CO 2 H, -CH 2 -OH, -CH 2 -SH, -CH=CH-R 5 , -CH 2 -R 5 , -CH 2 -SR 5 , -CH 2 -N(R 4 )-R 5 , -CH 2 -N(R 4 )-C(O)-R 5 , -CH 2 -N(R 4 )-C(O)-OR 5 , -CH 2 -N(R 4 )-C(O)-N(R 4 )-R 5 , -CH 2 -OR 5 , -CH 2 -OC(O)-R 5 , -CH 2 -OC(O)-N (R 4 )-R 5 , -CH 2 -OC(O)-OR 5 , -CH 2 -S(O)-R 5 , -CH 2 -S(O) 2 -R 5 , -CH 2 -S (O) 2 -N(R 4 )-R 5 , -C(O)-NH 2 , -C(O)-OR 5 , -C(O)-N(R 4 )-R 5 , -S( O) 3 H, -S(O) 2 Cl, -S(O) 2 F, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by R 5 or R 1 -ZXY , -ZY, -XY, -X, -Y or -ZX, wherein the X-type linker or drug delivery system, the Y-line R 6 or is selected from the group consisting of small molecules, amino acid sequences, nucleic acid sequences, antibodies, oligomers a polymer, a gene-derived material, a liposome, a nanoparticle, a dye, a fluorescent probe, or a combination thereof, and the Z-system -C≡C-, -CH=CH-, -CH 2 - , -CH 2 -O-, -C(O)-N(R 4 )-, -CH 2 -S-, -CH 2 -S(O)-,- CH 2 -S(O) 2 -, -CH 2 -S(O) 2 -N(R 4 )-, -C(O)-O-, -CH 2 -N(R 4 )-, -CH 2 -N(R 4 )-C(O)-, -CH 2 -N(R 4 )-S(O) 2 -, -CH 2 -N(R 4 )-C(O)-O-, -CH 2 -N(R 4 )-C(O)-N(R 4 )-, -CH 2 -OC(O)-, -CH 2 -OC(O)-N(R 4 )-, -CH 2 - OC(O)-O-, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted by R 5 ; R 2 is -OH, -N 3 , -N(R 3 ) 2 , - N(R 3 )-C(O)-R 3 , -N(R 3 )-C(O)-N(R 3 ) 2 , -N(R 3 )-C(O)-OR 3 , -N (R 3 )-S(O) 2 -R 3 , tetrazole or triazole, wherein the tetrazole and triazole are optionally substituted by R 3 , and wherein when R 1 is —CH 2 —OH, R 2 -N 3 , -N(R 3 ) 2 , -N(R 3 )-C(O)-R 3 , -N(R 3 )-C(O)-N(R 3 ) 2 , -N( R 3 )-C(O)-OR 3 , -N(R 3 )-S(O) 2 -R 3 , tetrazole or triazole, wherein the tetrazole and triazole are optionally substituted by R 3 ; And each R 3 is -H, -(C 1 -C 5 )alkyl, substituted by halogen (C 1 -C 5 )alkyl, or (C 3 -C 6 )cycloalkyl, wherein the alkyl group Or one or more -CH 2 - groups of the cycloalkyl group may each be replaced by a hetero atom group independently selected from -O-, -S- or -N(R 4 )- and the -CH 3 group of the alkyl group Can be selected from -N(R 4 ) a hetero atom radical substitution of 2 , -OR 4 or -S(R 4 ) wherein the hetero atom radicals are separated by at least 2 carbon atoms; each R 4 is independently -H, -(C 1 -C 20 An alkyl or (C 3 -C 6 )cycloalkyl group wherein 1 to 6 -CH 2 - groups of the alkyl or cycloalkyl group separated by at least 2 carbon atoms may each independently be selected from -O a hetero atom substituted with -, -S- or -N(R 4 )- and the -CH 3 group of the alkyl group may be selected from the group consisting of -N(R 4 ) 2 , -OR 4 or -S(R 4 ) Atomic radical substitution wherein the heteroatomic radicals are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl groups are substituted by 1 to 6 halogen atoms; each R 5 is independently -H, ( C 3 -C 20 )cycloalkyl or (C 1 -C 60 )alkyl, wherein 1 to 6 -CH 2 - groups of the cycloalkyl group or 1 to 20 -CH 2 - groups of the alkyl group may be Each is replaced by a hetero atom independently selected from -O-, -S- or -N(R 4 )-, wherein the heteroatoms are separated by at least 2 carbon atoms and the -CH 3 group of the alkyl group Substituting a hetero atom radical selected from -N(R 4 ) 2 , -OR 4 or -S(R 4 ) wherein the heteroatoms are separated by at least 2 carbon atoms; and wherein the alkyl group A cycloalkyl group can be substituted by a halogen atom And each R 6 is individually H, -C≡CH, -C = CH 2 , -CH 3, -N 3, -N (R 4) 2, -OH, -S (O) - (R 4) , -S(O) 2 -(R 4 ), -C(O)-OH, -SS-aryl, -SS-heteroaryl, heterocyclyl, aryl or heteroaryl, wherein each aryl aryl or heteroaryl group optionally substituted with R 5; or a pharmaceutically he of the pharmaceutically acceptable salt thereof.

本發明之另一方面包括醫藥組成物，其包含(i)式(A)化合物和(ii)醫藥上可接受之賦形劑、稀釋劑或載劑。Another aspect of the invention includes a pharmaceutical composition comprising (i) a compound of formula (A) and (ii) a pharmaceutically acceptable excipient, diluent or carrier.

本發明之另一方面包括一種治療肝臟疾病或症狀或肝臟調節的疾病或症狀之方法，該疾病或症狀包括遺傳性血管性水腫、家族性第1型酪胺酸血症、艾拉基爾(Alagille)氏症候群、α-1-抗胰蛋白酶缺乏症、膽酸合成與代謝不全、膽管閉鎖、囊性纖維變性肝臟疾病、自發性新生兒肝炎、粒線體性肝疾、進行性家族性肝內膽汁鬱積、原發性 硬化性膽管炎、甲狀腺素運載蛋白澱粉樣變性、血友病、同基因組合型家族性高膽固醇血症、高脂血症、脂肪變性肝炎、非酒精性脂肪變性肝炎(NASH)、非酒精性脂肪肝疾病(NAFLD)、似高血糖症第2型糖尿病及涉及與第2型糖尿病相似之異常高肝臟葡萄糖生成的疾病，該方法包含投予有效量之任何式(A)化合物或彼之醫藥上可接受之鹽。Another aspect of the invention includes a method of treating a liver disease or condition or a liver-regulated disease or condition, including hereditary angioedema, familial type 1 tyrosinemia, or ilaquille ( Alagille syndrome, alpha-1-antitrypsin deficiency, bile acid synthesis and metabolic insufficiency, bile duct atresia, cystic fibrosis liver disease, spontaneous neonatal hepatitis, mitochondrial liver disease, progressive familial liver Internal cholestasis, primary Sclerosing cholangitis, thyroxine carrier protein amyloidosis, hemophilia, isogenic combination familial hypercholesterolemia, hyperlipidemia, steatosis hepatitis, nonalcoholic steatosis hepatitis (NASH), nonalcoholic Fatty liver disease (NAFLD), hyperglycemia type 2 diabetes, and diseases involving abnormally high hepatic glucose production similar to type 2 diabetes, the method comprising administering an effective amount of any of the compounds of formula (A) or the drug thereof Acceptable salt.

本發明之另一方面包括式(B)化合物： Another aspect of the invention includes a compound of formula (B):

或彼之醫藥上可接受之鹽。Or a pharmaceutically acceptable salt thereof.

本發明之另一方面包括式(C)化合物： Another aspect of the invention includes a compound of formula (C):

或彼之醫藥上可接受之鹽。Or a pharmaceutically acceptable salt thereof.

本發明之另一方面包括式(D)化合物： Another aspect of the invention includes a compound of formula (D):

或彼之醫藥上可接受之鹽。Or a pharmaceutically acceptable salt thereof.

進一步，本發明之另一方面包括式(E)化合物： Further, another aspect of the invention includes a compound of formula (E):

或彼之醫藥上可接受之鹽。Or a pharmaceutically acceptable salt thereof.

進一步，本發明之另一方面包括式(F)化合物： Further, another aspect of the invention includes a compound of formula (F):

或彼之醫藥上可接受之鹽。Or a pharmaceutically acceptable salt thereof.

進一步，本發明之另一方面包括式(G)化合物： Further, another aspect of the invention includes a compound of formula (G):

或彼之醫藥上可接受之鹽。Or a pharmaceutically acceptable salt thereof.

進一步，本發明之另一方面包括式(H)化合物： Further, another aspect of the invention includes a compound of formula (H):

或彼之醫藥上可接受之鹽。Or a pharmaceutically acceptable salt thereof.

應當瞭解的是：前揭一般敘述和下述詳細說明皆僅為例示性和說明性且非為如申請專利範圍所揭露之本發明的限制。It is to be understood that the foregoing general description and the appended claims

發明詳細說明Detailed description of the invention

藉由參照下述本發明的例示性實施態樣和彼所包括之實施例的詳細說明，可較容易地瞭解本發明。The invention may be readily understood by reference to the following detailed description of exemplary embodiments of the invention,

於揭露和描述本發明之化合物、組成物及方法之前，應當瞭解的是：本發明不受限於特定之製備合成方法，該方法當然可變化。亦應當瞭解的是：本文所使用之術語係僅為描述特定之實施態樣且非作為限制。除非對數字之說明，複數和單數之描述應被視為可互換。Before exposing and describing the compounds, compositions, and methods of the present invention, it should be understood that the invention is not limited to the particular synthetic methods of preparation, which may of course vary. It should be understood that the terminology used herein is for the purpose of description Unless stated in the figures, the description of the plural and singular shall be construed as interchangeable.

本文所使用之“烷基”係指通式Cn H2n+1 之烴基。烷基可為直鏈或支鏈。例如，“(C1 -C6 )烷基”係指含有1至6個碳原子之單價直鏈或支鏈脂肪族基(例如甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基、三級丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、3,3-二甲基丙基、己基、2-甲基戊基及類似基)。同樣地，烷氧基、醯基(例如烷醯基)、烷基胺基、二烷基胺基、烷基磺醯基及烷硫基之烷基部分具有如上述相同之定義。當表示為“可選擇地經取代”時，該烷基或烷基部分可未經取代或經1或多個取代基(通常1至3個取代基；除了鹵素取代基以外(諸如全氯或全氟烷基))取代，該等取代基獨立地選自下述“經取代”之定義所列示的取代基。“經 鹵素取代之烷基”係指經1或多個鹵素原子取代之烷基(例如氟甲基、二氟甲基、三氟甲基、全氟乙基、1,1-二氟乙基及類似基)。As used herein, the "alkyl" means a hydrocarbyl group of formula C n H 2n + 1 used. The alkyl group can be straight or branched. For example, "(C 1 -C 6 )alkyl" means a monovalent straight or branched aliphatic group containing from 1 to 6 carbon atoms (eg methyl, ethyl, n-propyl, isopropyl, n-butyl) Base, isobutyl, secondary butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-di Methylpropyl, hexyl, 2-methylpentyl and the like). Similarly, the alkyl moiety of an alkoxy group, a fluorenyl group (e.g., an alkyl fluorenyl group), an alkylamino group, a dialkylamino group, an alkyl sulfonyl group, and an alkylthio group has the same definition as described above. When expressed as "optionally substituted," the alkyl or alkyl moiety can be unsubstituted or substituted with one or more substituents (typically 1 to 3 substituents; in addition to a halogen substituent (such as perchlorine or Perfluoroalkyl)) substituted, the substituents are independently selected from the substituents listed in the definition of "substituted" below. "Alkyl substituted by halogen" means an alkyl group substituted by one or more halogen atoms (for example, fluoromethyl, difluoromethyl, trifluoromethyl, perfluoroethyl, 1,1-difluoroethyl) And similar base).

同樣地，“伸烷基”係指通式Cn H2n 之二價烴基，其可為直鏈或支鏈。Similarly, "Alkylene" refers to the general formula C n H 2n divalent hydrocarbon group which may be straight-chain or branched.

“烯基”係指含有1或多個碳碳雙鍵之單價不飽和烴基。該烯基部分可為直鏈或支鏈。烯基之實例包括乙烯基。本文所使用之“伸烯基”係指含有1或多個碳碳雙鍵且可為直鏈或支鏈之二價不飽和烴基。"Alkenyl" means a monovalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds. The alkenyl moiety can be straight or branched. Examples of alkenyl groups include vinyl groups. As used herein, "alkenyl" refers to a divalent unsaturated hydrocarbon group containing one or more carbon-carbon double bonds and which may be straight or branched.

“炔基”係指含有1或多個碳碳三鍵之單價不飽和烴基。該炔基部分可為直鏈或支鏈。本文所使用之“伸炔基”係指含有1或多個碳碳三鍵且可為直鏈或支鏈之二價不飽和烴基。"Alkynyl" means a monovalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds. The alkynyl moiety can be straight or branched. As used herein, "extended alkynyl" refers to a divalent unsaturated hydrocarbon group containing one or more carbon-carbon triple bonds and which may be straight or branched.

“芳基”表示含有1、2或3個環之芳香族碳環系統，其中該等環可經稠合。若該等環係經稠合，則該等環之一者必須為完全不飽和且該(等)經稠合之環可為完全飽和、部分不飽和或完全不飽和。“稠合”表示存在第2個環，即藉由與第1個環共有(即分享)2個相鄰原子以連接或形成該第2個環。該“稠合”等同於“縮合”。“芳基”包含芳香族基，諸如苄基、苯基、萘基、四氫萘基、二氫茚基、聯苯基、苯並[b][1,4]噁嗪-3(4H)-酮基、2,3-二氫-1H-茚基及1,2,3,4-四氫萘基。"Aryl" means an aromatic carbocyclic ring system containing 1, 2 or 3 rings wherein the rings may be fused. If the rings are fused, one of the rings must be completely unsaturated and the (other) fused ring can be fully saturated, partially unsaturated or fully unsaturated. "Fused" means the presence of a second loop, i.e., by sharing (i.e., sharing) two adjacent atoms with the first loop to join or form the second loop. This "fused" is equivalent to "condensation". "Aryl" includes an aromatic group such as benzyl, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, benzo[b][1,4]oxazine-3 (4H) a keto group, a 2,3-dihydro-1H-indenyl group and a 1,2,3,4-tetrahydronaphthyl group.

“環烷基”係指完全氫化之非芳香族環，其可為單環、雙環或螺環。除非另有特別指明，該碳環通常為3至20 員環。例如，環烷基包括諸如環丙基、環丁基、環戊基、環己基、環己烯基、原冰片烷基(雙環[2.2.1]庚基)、雙環[2.2.2]辛基及類似基。"Cycloalkyl" means a fully hydrogenated non-aromatic ring which may be monocyclic, bicyclic or spiro. Unless otherwise specified, the carbon ring is usually 3 to 20 Member ring. For example, cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl And similar bases.

“雜芳基”表示含有1、2、3或4個雜原子和1、2或3個環之芳香族碳環系統，其中該等雜原子獨立選自氧(O)、氮(N)或硫(S)且其中該等環可經稠合，其中該稠合係如上述所定義者。該“雜芳基”包括但不限於呋喃基、噻吩基、噁唑基、噻唑基、咪唑基、吡唑基、***基、四唑基、異噁唑基、異噻唑基、噁二唑基、噻二唑基、吡啶基、噠嗪基、嘧啶基、吡嗪基、吡啶-2(1H)-酮基、噠嗪-2(1H)-酮基、嘧啶-2(1H)-酮基、吡嗪-2(1H)-酮基、咪唑並[1,2-a]吡啶基、吡唑並[1,5-a]吡啶基、5,6,7,8-四氫異喹啉基、5,6,7,8-四氫喹啉基、6,7-二氫-5H-環戊並[b]吡啶基、6,7-二氫-5H-環戊並[c]吡啶基、1,4,5,6-四氫環戊並[c]吡唑基、2,4,5,6-四氫環戊並[c]吡唑基、5,6-二氫-4H-吡咯並[1,2-b]吡唑基、6,7-二氫-5H-吡咯並[1,2-b][1,2,4]***基、5,6,7,8-四氫-[1,2,4]***並[1,5-a]吡啶基、4,5,6,7-四氫吡唑並[1,5-a]吡啶基、4,5,6,7-四氫-1H-吲唑基及4,5,6,7-四氫-2H-吲唑基。"Heteroaryl" means an aromatic carbocyclic ring system containing 1, 2, 3 or 4 heteroatoms and 1, 2 or 3 rings, wherein the heteroatoms are independently selected from the group consisting of oxygen (O), nitrogen (N) or Sulfur (S) and wherein the rings may be fused, wherein the fused system is as defined above. The "heteroaryl" includes, but is not limited to, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazole , thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridine-2(1H)-one, pyridazine-2(1H)-one, pyrimidine-2(1H)-one , pyrazine-2(1H)-keto, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, 5,6,7,8-tetrahydroisoquine Lolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, 6,7-dihydro-5H-cyclopenta[c] Pyridyl, 1,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, 5,6-dihydro- 4H-pyrrolo[1,2-b]pyrazolyl, 6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazolyl, 5,6,7, 8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 4, 5,6,7-tetrahydro-1H-carbazolyl and 4,5,6,7-tetrahydro-2H-carbazolyl.

“藥物投遞系統”係指投遞治療有效量之配體的機構且包括但不限於聚合物(諸如PEG(聚(乙二醇)甲醚)、PEG-PLA(聚(乙二醇)甲醚-聚(D,L乳酸交酯))、PEG-PLGA(聚(乙二醇)甲醚-聚(乳酸交酯-共乙交酯))及PEG-PCL(聚(乙二醇)-聚(ε-己內酯)甲醚))、量子點(Quantum Dots；Q dots)、脂質體、免疫脂質體、微膠粒、奈米粒子及奈米膠。藥物投遞系統之實例係描述於文獻Tiwari,G.,“Drug Delivery Systems：an Updated Review”,Int.J.Pharm.Investig.,2(1)：2-11(2012年1月)，該文獻為所有目的係併入本文作為參考。"Drug delivery system" refers to a mechanism for delivering a therapeutically effective amount of a ligand and includes, but is not limited to, a polymer such as PEG (poly(ethylene glycol) methyl ether), PEG-PLA (poly(ethylene glycol) methyl ether- Poly(D,L lactide)), PEG-PLGA (poly(ethylene glycol) methyl ether-poly(lactide-co-glycolide)) and PEG-PCL (poly(ethylene glycol)-poly( Ε-caprolactone) methyl ether)), quantum dots (Quantum Dots; Q Dots), liposomes, immunoliposomes, micelles, nanoparticles and nanogels. Examples of drug delivery systems are described in the literature Tiwari, G., "Drug Delivery Systems: Updated Updated", Int. J. Pharm. Investig., 2(1): 2-11 (January 2012), the document All of the objects are incorporated herein by reference.

“小分子”表示分子量介於100至2000道耳頓(dalton)之有機化合物，其包括但不限於合成化合物和天然產物。"Small molecule" means an organic compound having a molecular weight between 100 and 2000 daltons including, but not limited to, synthetic compounds and natural products.

“抗體”係免疫球蛋白分子，該免疫球蛋白分子藉由位於彼之可變區的至少一個抗原辨識部位能與標的(諸如碳水化合物、多核苷酸、脂質、多肽等)專一性結合。本文所使用之“抗體”不僅包含完整之多株或單株抗體且亦包含彼等之片段(諸如Fab、Fab’、F(ab’)2 、Fv、單鏈抗體(ScFv)及結構域抗體)、包含抗體部分之融合蛋白、及包含抗原辨識部位之免疫球蛋白分子的任何其他經修飾之構形。抗體包括任何類型之抗體(諸如IgG、IgA或IgM(或彼等之次類型))且該抗體不需屬任何特定之類型。取決於抗體之重鏈的恆定結構域之胺基酸序列，免疫球蛋白可被區分為不同之類型。免疫球蛋白有5種主要之類型：IgA、IgD、IgE、IgG及IgM，且該等類型中數者可被進一步區分成數種次類型(同型)，例如IgG1、IgG2、IgG3、IgG4、IgA1及IgA2。對應不同類型之免疫球蛋白的重鏈恆定結構域被分別稱為α、δ、ε、γ及μ。不同類型之免疫球蛋白的次單位結構和3維構形係為習知。An "antibody" is an immunoglobulin molecule that is capable of specifically binding to a subject (such as a carbohydrate, polynucleotide, lipid, polypeptide, etc.) by at least one antigen recognition site located in the variable region of the other. As used herein, "antibody" includes not only intact multi-strain or monoclonal antibodies but also fragments thereof (such as Fab, Fab', F(ab') 2 , Fv, single-chain antibody (ScFv) and domain antibodies. a fusion protein comprising an antibody portion, and any other modified configuration of an immunoglobulin molecule comprising an antigen recognition site. Antibodies include any type of antibody (such as IgG, IgA or IgM (or subtypes thereof)) and the antibody does not need to be of any particular type. Immunoglobulins can be distinguished into different types depending on the amino acid sequence of the constant domain of the heavy chain of the antibody. There are five main types of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and the number of these types can be further divided into several subtypes (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to different types of immunoglobulins are referred to as α, δ, ε, γ, and μ, respectively. The subunit structure and the three-dimensional conformation system of different types of immunoglobulins are conventional.

本文所使用之“單株抗體”係指得自實質均質抗體群之 抗體，即包含該群之個別抗體為相同，唯極少數可能存有天然發生之可能突變。單株抗體係高度專一性，其針對單一抗原部位。進一步，相對於典型上包括針對不同決定部位(抗原決定位)之不同抗體的多株抗體製劑，每個單株抗體係針對抗原之單一決定部位。修飾語“單株”表示該抗體之特性係得自實質均質抗體群且不被解釋為需要由任一特定方法所產製之抗體。例如，依據本發明所使用之單株抗體可藉由首先由文獻Kohler and Milstein,1975,Nature 256：495所描述之融合瘤方法製備或可藉由諸如美國專利號4,816,567所描述之重組DNA方法製備。亦可自使用例如文獻McCafferty et al.,1990,Nature 348：552-554描述之技術所產製之噬菌體庫分離單株抗體。As used herein, "monoclonal antibody" refers to a group derived from a substantially homogeneous antibody. The antibodies, ie the individual antibodies comprising the group, are identical, and very few may have naturally occurring possible mutations. The monoclonal antibody system is highly specific and targets a single antigenic site. Further, each monoclonal antibody system is directed against a single epitope of the antigen relative to a plurality of antibody preparations that typically include different antibodies directed against different epitopes (antigenic epitopes). The modifier "single plant" indicates that the properties of the antibody are derived from a population of substantially homogeneous antibodies and are not to be construed as requiring antibodies produced by any particular method. For example, a monoclonal antibody used in accordance with the present invention may be prepared by a fusion method first described by the literature Kohler and Milstein, 1975, Nature 256:495 or may be prepared by recombinant DNA methods such as those described in U.S. Patent No. 4,816,567. . Individual antibodies can also be isolated from phage libraries produced by techniques such as those described in the literature by McCafferty et al., 1990, Nature 348:552-554.

抗體之“可變區”係指抗體輕鏈之可變區或抗體重鏈之可變區，單獨或彼等之組合。如此技術所習知者，重鏈和輕鏈之可變區各別係由與4個構架區(FR)連接之3個互補決定區(CDR)所構成，該等CDR含有高度可變區。每條鏈之該等CDR係與該等FR鄰近緊密連接且與另一鏈之3個CDR構成抗體之抗原結合部位。至少有2種技術可測定CDR：(1)基於跨物種之序列可變性的方法(即文獻Kabat et al.,“Sequences of Proteins of Immunological Interest”,第5版，1991,National Institutes of Health,Bethesda MD)和(2)基於抗原-抗體複合物之晶體研究的方法(即文獻Al-lazikani et al.,1997,J.Molec.Biol.,273：927-948)。本文所使用之CDR可指由該兩種方法之一或彼等之組合所定 義之CDR。"Variable region" of an antibody refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, either alone or in combination. As is known in the art, the variable regions of the heavy and light chains are each composed of three complementarity determining regions (CDRs) joined to four framework regions (FR), which contain highly variable regions. The CDR lines of each chain are in close proximity to the FRs and the three CDRs of the other chain constitute the antigen binding site of the antibody. There are at least two techniques for determining CDRs: (1) methods based on sequence variability across species (ie, Kabat et al., "Sequences of Proteins of Immunological Interest", 5th edition, 1991, National Institutes of Health, Bethesda MD) and (2) methods for crystal research based on antigen-antibody complexes (i.e., literature Al-lazikani et al., 1997, J. Molec. Biol., 273: 927-948). A CDR as used herein may refer to one or a combination of the two methods. CDR of righteousness.

如此技術所習知者，抗體之“恆定區”係指抗體輕鏈之恆定區或抗體重鏈之恆定區，單獨或彼等之組合。As is known in the art, the "constant region" of an antibody refers to the constant region of the antibody light chain or the constant region of the antibody heavy chain, either alone or in combination.

“治療有效量”表示本發明之化合物的用量，該用量(1)治療本文所述特定之疾病、症狀或失調、(2)減輕、緩和或除去該特定之疾病、症狀或失調的一或多個徵候、或(3)預防或遲延該特定之疾病、症狀或失調的一或多個徵候之開始。"Therapeutically effective amount" means an amount of a compound of the invention which (1) treats a particular disease, condition or disorder described herein, (2) reduces, alleviates or removes one or more of the particular disease, condition or disorder. a sign, or (3) the beginning of one or more signs of preventing or delaying the particular disease, condition, or disorder.

“動物”係指人(男性或女性)、陪伴動物(例如狗、貓及馬)、食物來源動物、動物園動物、海洋動物、鳥類及其他類似之動物物種。“可食用性動物”係指食物來源動物，諸如牛、豬、羊及禽。"Animal" means human (male or female), companion animals (eg, dogs, cats, and horses), food-derived animals, zoo animals, marine animals, birds, and other similar animal species. "Edible animal" means a food-derived animal such as cattle, pigs, sheep and poultry.

“醫藥上可接受”表示物質或組成物必須與調製劑所包含之其他成分及/或使用彼治療之哺乳動物在化學上及/或毒物學上相容。"Pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients included in the modulator and/or the mammal to which it is treated.

“治療”或“處理”或“處置”包含預防性(即預防治療性)和舒緩療性之治療、處理或處置。"Treatment" or "treatment" or "disposal" encompasses the treatment, treatment or treatment of prophylactic (ie, prophylactic) and soothing.

本文所使用之“醫藥上可接受之載劑”或“醫藥上可接受之賦形劑”包括與活性成分組合時能使該成分保留彼之生物活性且不與個體之免疫系統反應的任何材料。實例包括但不限於任何標準醫藥載劑，諸如磷酸鹽緩衝溶液、水、乳化液(諸如油/水乳化液)及各種類型之潤濕劑。用於氣溶膠或非經腸投予之較佳稀釋劑係磷酸鹽緩衝鹽水(PBS)或標準鹽水(0.9%)。包含該等載劑之組成物係經習 知之慣用方法調劑(參閱例如文獻Remington's Pharmaceutical Sciences，第18版，A.Gennaro,ed.,Mack Publishing Co.,Easton,PA,1990；Remington,The Science and Practice of Pharmacy，第20版，Mack Publishing,2000)。As used herein, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any material which, when combined with the active ingredient, will retain the biological activity of the component and will not react with the immune system of the individual. . Examples include, but are not limited to, any standard pharmaceutical carrier, such as a phosphate buffer solution, water, an emulsion (such as an oil/water emulsion), and various types of wetting agents. A preferred diluent for aerosol or parenteral administration is phosphate buffered saline (PBS) or standard saline (0.9%). The composition containing the carriers is a Known method adjustments (see, for example, Remington's Pharmaceutical Sciences, 18th Edition, A. Gennaro, ed., Mack Publishing Co., Easton, PA, 1990; Remington, The Science and Practice of Pharmacy, 20th Edition, Mack Publishing, 2000).

“本發明之化合物”(除非另有特別說明)係指式(A)化合物和所有鏡像異構物、互變異構物及經同位素標記之化合物。本發明之化合物的水合物和溶劑化物被視為本發明之組成物，其中該化合物分別與水或溶劑結合。該化合物亦可以一或多種結晶態(即共晶體和多晶形)存在或可以非晶形固體存在。申請專利範圍包含所有該等形式。"Compound of the invention" (unless otherwise specifically indicated) refers to a compound of formula (A) and all enantiomers, tautomers and isotopically labeled compounds. Hydrates and solvates of the compounds of the invention are considered to be compositions of the invention wherein the compounds are combined with water or a solvent, respectively. The compound may also be present in one or more crystalline states (i.e., co-crystals and polymorphs) or may be present as an amorphous solid. The scope of application for patents covers all such forms.

“連接子”係經由至少一個共價鍵與一或多個其他化學基團連接之化學基團。連接子可包括一或多個間隔基，該等間隔基包括但不限於伸烷基、伸烯基、伸炔基、烷基、烯基、炔基、烷氧基、芳基、雜芳基、芳烷基、芳烯基、芳炔基及類似基。連接子可呈電荷中性、電荷陽性或電荷陰性。此外，連接子可為可切割者，使得該連接子之共價鍵於某些條件下可被打斷或切割，其中該共價鍵使該連接子與該連接子內另一化學基團連接或與配體鍵結(參閱文獻例如H.Bruyere,et al.,“Tuning the pH Sensitivities of Orthoester based compounds for Drug Delivery Applications by Simple Chemical Modification”,B ioorganic and Medicinal Chemistry Letters,20,2200(2010)和A.A.Kislukhin et al.,“Degradable Conjugates from Oxanorbornadiene Reagents”,Journal of the American Chemical Society,134,6491(2012))。該等條件包括pH、溫度、鹽濃度、觸媒或酶(參閱文獻G.M.Dubowchik et al.,“Cathepsin B-Labile Dipeptide Linkers for Lysosomal Release of Doxorubicin from Internalizing Immunoconjugates：Model Studies of Enzymatic Drug Release and Antigen-Specific In Vitro Anticancer Activity”,Bioconjugate Chemistry,13,855(2002)；G.Leriche et al.,“Cleavable Linkers in Chemical Biology”,Bioorganic and Medicinal Chemistry,20,571(2012)；C.P.R.Hackenberger et al.,“Chemoselective Ligation and Modification Strategies for Peptides and Proteins”,Angewandte Chemie International Edition,47,10030(2008)；D.M.Patterson et al.,“Finding the Right (Bioorthogonal)Chemistry”,ACS Chemical Biology,9,592(2014)；C.A.Blencowe et al.,“Self-immolative Linkers in Polymeric Delivery Systems”,Polymer Chemistry,2,773(2011))。上述文獻所揭露之全部內容基於所有目的併入本文作為參考。A "linker" is a chemical group attached to one or more other chemical groups via at least one covalent bond. The linker may include one or more spacers including, but not limited to, alkyl, alkenyl, alkynyl, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl , aralkyl, aralkenyl, aralkynyl and the like. The linker can be charge neutral, charge positive or charge negative. Furthermore, the linker can be a cleavable such that the covalent bond of the linker can be cleaved or cleaved under certain conditions, wherein the covalent bond links the linker to another chemical group within the linker Or with a ligand (see, for example, H. Bruyere, et al., "Tuning the pH Sensitivities of Orthoester based compounds for Drug Delivery Applications by Simple Chemical Modification", B ioorganic and Medicinal Chemistry Letters, 20, 2200 (2010) And AAKislukhin et al., "Degradable Conjugates From Oxanorbornadiene Reagents", Journal of the American Chemical Society, 134, 6491 (2012). These conditions include pH, temperature, salt concentration, catalyst or enzyme (see GMDubowchik et al., "Cathepsin B-Labile Dipeptide" Linkers for Lysosomal Release of Doxorubicin from Internalizing Immunoconjugates: Model Studies of Enzymatic Drug Release and Antigen-Specific In Vitro Anticancer Activity", Bioconjugate Chemistry, 13, 855 (2002); G. Leriche et al., "Cleavable Linkers in Chemical Biology", Bioorganic And Medicinal Chemistry, 20, 571 (2012); CPR Hackenberger et al., "Chemoselective Ligation and Modification Strategies for Peptides and Proteins", Angewandte Chemie International Edition, 47, 10030 (2008); DMPatterson et al., "Finding the Right ( Bioorthogonal) Chemistry", ACS Chemical Biology, 9, 592 (2014); CA Blencowe et al., "Self-immolative Linkers in Polymeric Delivery Systems", Polymer Chemistry, 2, 773 (2011). The entire disclosure of the above references is based on all purposes. Incorporate this article as a reference test.

於某些實施態樣中，該連接子於細胞內條件下可被切割，使得於細胞內環境下，該連接子之切割自式A化合物釋出配體單位。於某些實施態樣中，藉由存在於細胞內環境(例如於溶酶體、胞內體或胞膜窖內)之切斷試劑使該連接子可被切割。可被切割之連接子的一個實例係可被酶催 化切割之連接子(即肽基連接子)，該連接子被細胞內肽酶或蛋白酶切割，該等酶包括但不限於溶酶體或胞內體蛋白酶。於某些實施態樣中，該肽基連接子係至少2個胺基酸長或至少3個胺基酸長。酶催化切割試劑包括細胞自溶酶B和D及胞漿素，所有上述皆習知能水解二肽藥物衍生物以致使標的細胞內之活性藥物釋出(參閱文獻Dubowchik,Gene M.et al.,Cathepsin B-Labile Dipeptide Linkers for Lysosomal Release of Doxorubicin,Bioconjugate Chem.2002,13,855-869)。該等連接子包括肽和二肽，該等肽和二肽包括上述文獻所描述者，該等文獻之全部內容基於所有目的併入本文作為參考。In certain embodiments, the linker can be cleaved under intracellular conditions such that the cleavage of the linker releases the ligand unit from the compound of formula A in an intracellular environment. In certain embodiments, the linker can be cleaved by a cleavage reagent present in the intracellular environment (e.g., within lysosomes, endosomes, or membranes). An example of a linker that can be cleaved can be enzymatically A cleavage linker (i.e., a peptidyl linker) that is cleaved by an intracellular peptidase or protease, including but not limited to lysosomal or endosomal proteases. In certain embodiments, the peptidyl linker is at least 2 amino acids long or at least 3 amino acids long. Enzyme-catalyzed cleavage reagents include cellular autolysing enzymes B and D and cytosolic, all of which are known to hydrolyze dipeptide drug derivatives to release active drugs in the target cells (see Dubowchik, Gene M. et al., Cathepsin B-Labile Dipeptide Linkers for Lysosomal Release of Doxorubicin, Bioconjugate Chem. 2002, 13, 855-869). Such linkers include peptides and dipeptides, which are described in the above-referenced references, the entire contents of each of which are hereby incorporated by reference.

其他可被切斷之連接子可被親核性/鹼性反應劑、還原性反應劑、光照射及親電子性/酸性反應劑切割(參閱文獻Leriche,Geoffray,et al.,Cleavable Linkers in Chemical Biology,Bioorganic & Medicinal Chemistry 20(2012)571-582)。Other linkers that can be cleaved can be cleaved by nucleophilic/alkaline reactants, reducing reactants, light irradiation, and electrophilic/acidic reagents (see literature by Lereche, Geoffray, et al., Cleavable Linkers in Chemical) Biology, Bioorganic & Medicinal Chemistry 20 (2012) 571-582).

再於另一實施態樣中，連接子單位不可被切割且藉由降解自式A化合物釋出藥物。此方法通常被稱為自我犧牲式(self-immolative)除去，該除去係藉由熵和熱動力學所驅動之環化反應或電子級聯反應進行。非可切割之連接子的一個實例係經多取代之富含電子的芳香族物種，其含有胺基或羥基或其他供電子基，該基與於苄基位置之離去基共軛(參閱文獻Blencowe,Christopher A.et al.,Self-immolative Linkers in Polymeric Delivery Systems, Polymer Chemistry,2011,2,773-790)。自我犧牲式除去之連接子包括但不限於以苯胺為底之連接子、以N-羥基苯胺為底之連接子、以酚為底之連接子、以1,8-除去為底之連接子、以環化為底之連接子(即以羥基為底之連接子、以胺基為底之連接子及以巰基為底之連接子)、聚合物-樹突共軛物及聚合物共軛物(即N-(2-羥基丙基)-甲基丙烯醯胺(HPMA)聚合物共軛物、聚乙二醇(PEG)聚合物共軛物)(參閱文獻I.Tranoy-Opalinski,et al.,Design of Self-Immolative Linkers for Tumour-Activated Prodrug Therapy,Anti-Cancer Agents in Medicinal Chemistry,2008,8,618-637；Blencowe,Christopher A.et al.,Self-immolative Linkers in Polymeric Delivery Systems,Polymer Chemistry,2011,2,773-790)。In yet another embodiment, the linker unit is not cleaved and the drug is released from the compound of formula A by degradation. This method is commonly referred to as self-immolative removal, which is carried out by enzymatic or thermodynamically driven cyclization or electronic cascade reactions. An example of a non-cleavable linker is a multi-substituted electron-rich aromatic species containing an amine group or a hydroxyl group or other electron-donating group conjugated to a leaving group at the benzylic position (see literature) Blencowe, Christopher A. et al., Self-immolative Linkers in Polymeric Delivery Systems, Polymer Chemistry, 2011, 2, 773-790). Self-sacrifice-removed linkers include, but are not limited to, an aniline-based linker, an N-hydroxyaniline-based linker, a phenol-based linker, a 1,8-removal-based linker, a cyclization-based linker (ie, a hydroxyl-based linker, an amine-based linker and a thiol-based linker), a polymer-dendritic conjugate, and a polymer conjugate (ie N-(2-hydroxypropyl)-methacrylamide (HPMA) polymer conjugate, polyethylene glycol (PEG) polymer conjugate) (Ref. I. Tranoy-Opalinski, et al) Design of Self-Immolative Linkers for Tumour-Activated Prodrug Therapy, Anti-Cancer Agents in Medicinal Chemistry, 2008, 8, 618-637; Blencowe, Christopher A. et al., Self-immolative Linkers in Polymeric Delivery Systems, Polymer Chemistry, 2011, 2, 773-790).

典型上，連接子於細胞外環境中本質上不被切割。對於連接子，本文所使用之“於細胞外環境中本質上不被切割”意謂：當包括X-Y基團之式A化合物存在於細胞外環境(例如血漿)中，於該化合物的樣品中不超過20%、典型地不超過約15%、較典型地不超過約10%及更較典型地不超過約5%、不超過約3%或不超過約1%之連接子被切割。藉由例如令該化合物與血漿經培育一段預定達至24小時(例如2、4、8、16或24小時)之時間並隨後定量存在於該血漿內之自由配體的量，可測定連接子是否於細胞外環境中本質上不被切割。Typically, the linker is not cleaved in nature in the extracellular environment. For a linker, as used herein, "not essentially cleaved in the extracellular environment" means that when a compound of formula A comprising an XY group is present in the extracellular environment (eg, plasma), it is not in the sample of the compound. More than 20%, typically no more than about 15%, more typically no more than about 10% and more typically no more than about 5%, no more than about 3%, or no more than about 1% of the linker is cleaved. The linker can be determined by, for example, incubating the compound with plasma for a period of up to 24 hours (e.g., 2, 4, 8, 16 or 24 hours) and then quantifying the amount of free ligand present in the plasma. Whether it is essentially not cut in the extracellular environment.

連接子可為單價、二價或三價分支連接子。於一實施 態樣中，連接子係二硫化物橋。於另一實施態樣中，連接子係結構L1至L10中任一者，該等結構L1至L10顯示Y與Z之連結(其中Y和Z代表如“發明簡述”所示之基團)： The linker can be a monovalent, divalent or trivalent branch linker. In one embodiment, the linker is a disulfide bridge. In another embodiment, the linker structures L1 to L10 are linked, and the structures L1 to L10 show a linkage of Y and Z (wherein Y and Z represent groups as shown in the "Summary of the Invention") :

其中每個T各別為不存在或伸烷基、伸烯基或伸炔基，其中該伸烷基、伸烯基或伸炔基之一或多個-CH2 -基可各別獨立地經雜原子基替代，該雜原子基獨立選自-O-、-S-或-N(R4 )-，其中該雜原子基係經至少2個碳原子分隔； 每個Q各別為不存在或C(O)、C(O)-NR4 、NR4 -C(O)、O-C(O)-NR4 、NR4 -C(O)-O、-CH2 -、雜芳基、或選自O、S、S-S、S(O)、S(O)2 或NR4 之雜原子基，其中該等雜原子基O、S、S-S、S(O)、S(O)2 及NR4 係與任何其他雜原子基間隔至少2個碳原子；每個R4 各別為-H、-(C1 -C20 )烷基或-(C3 -C6 )環烷基，其中該烷基或環烷基之經至少2個碳原子分隔的1至6個-CH2 -基團可經-O-、-S-或-N(R4 )-替代，且該烷基之-CH3 可經選自-N(R4 )2 、-OR4 或-S(R4 )之雜原子基替代，其中該等雜原子基係經至少2個碳原子分隔；且，其中該烷基和環烷基可經鹵素原子取代；且每個n各別為0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39或40。其中若n大於1，每個(T-Q-T-Q)之每個T和每個Q各別經選擇。Wherein each T is independently absent or alkyl, alkenyl or alkynyl, wherein the alkyl, alkenyl or alkynyl group or a plurality of -CH 2 - groups may independently Substituted by a hetero atom group, the hetero atom group is independently selected from -O-, -S- or -N(R 4 )-, wherein the hetero atom group is separated by at least 2 carbon atoms; each Q is not Exist or C(O), C(O)-NR 4 , NR 4 -C(O), OC(O)-NR 4 , NR 4 -C(O)-O, -CH 2 -, heteroaryl, Or a hetero atom group selected from O, S, SS, S(O), S(O) 2 or NR 4 wherein the hetero atom groups O, S, SS, S(O), S(O) 2 and NR 4 is separated from any other hetero atom by at least 2 carbon atoms; each R 4 is independently -H, -(C 1 -C 20 )alkyl or -(C 3 -C 6 )cycloalkyl, wherein 1 to 6 -CH 2 - groups of the alkyl or cycloalkyl group separated by at least 2 carbon atoms may be replaced by -O-, -S- or -N(R 4 )-, and the alkyl group -CH 3 may be replaced by a hetero atom radical selected from -N(R 4 ) 2 , -OR 4 or -S(R 4 ) wherein the heteroatoms are separated by at least 2 carbon atoms; The alkyl group and the cycloalkyl group may be substituted by a halogen atom; and each n is 0, 1, 2, 3, 4 , 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 , 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40. Where n is greater than 1, each T and each Q of each (TQTQ) are selected.

於一實施態樣中，Q係選自1H-1,2,3-***基、吡啶基或1,2,3,4-四唑基之雜芳基。In one embodiment, the Q system is selected from the group consisting of 1H-1,2,3-triazolyl, pyridyl or 1,2,3,4-tetrazolyl heteroaryl.

藉由n值可調節連接子長度至最適化可接近標的分子。於某些情況下，藉由分析藥物與標的交互作用之位置或適當地釋出該式(A)化合物所需之間隔，可設計該連接子之最佳長度。The length of the linker can be adjusted by the value of n to optimize the molecules that are accessible to the target. In some cases, the optimal length of the linker can be designed by analyzing the position of the interaction of the drug with the target or by appropriately releasing the desired spacing of the compound of formula (A).

“基因衍生性材料”意謂包括蛋白(其包括Cas9蛋白)、質體(其包括編碼該Cas9蛋白或cas9蛋白和引導序列之質 體)、RNA序列(諸如mRNA)、siRNA序列及Cas9核糖核蛋白。該Cas9核糖核蛋白可包括2個連結或鍵結之元件：(a)第一元件，其包含辨識元件，該辨識元件可包括追蹤子配偶序列和至少1個***至該追蹤子配偶序列前端之引導序列或單一引導序列(sgRNA)，其中當被表現時，該引導序列於真核細胞內引導該Cas9核糖核蛋白與標的序列之序列專一性結合、及(b)第二元件，其包含Cas9蛋白序列和可選擇地一或多個核定位序列(NLSs)，諸如約或超過約1、2、3、4、5、6、7、8、9、10或更多個NLSs。於某些實施態樣中，該第二元件於或接近胺基端或羧基端或彼等之組合處包含約1、2、3、4、5、6、7、8、9或10個NLSs(例如於胺基端一或多個NLS和於羧基端一或多個NLS)。當存在一或多個NLS時，每個NLS與其他NLS可被獨立地選擇，使得單一NLS可以超過1個複製數存在及/或可與以1或多個複製數存在之1或多個其他NLSs組合存在。“引導序列”係任何多核苷酸序列，該多核苷酸序列與標的多核苷酸序列具有充分之互補性而能與該標的序列雜交且引導Cas9核糖核蛋白與該標的序列之序列專一性結合。例示性Cas9蛋白、質體及核糖核蛋白係描述於US 20140068797(2014年3月6日公開)、US 2015031134(2015年1月29日公開)及US 2015079681(2015年3月19日公開)，該等專利申請案之全部內容基於所有目的併入本文作為參考。"Gene-derived material" is meant to include proteins (including Cas9 proteins), plastids (which include the quality of the Cas9 protein or cas9 protein and the leader sequence) , RNA sequences (such as mRNA), siRNA sequences, and Cas9 ribonucleoproteins. The Cas9 ribonucleoprotein may comprise two linked or bonded elements: (a) a first element comprising an identification element, the identification element comprising a tracking sub-spore sequence and at least one insertion into the front end of the tracking sub-sequence sequence a leader sequence or a single leader sequence (sgRNA), wherein when expressed, the leader sequence directs sequence specific binding of the Cas9 ribonucleoprotein to the target sequence in eukaryotic cells, and (b) a second element comprising Cas9 The protein sequence and optionally one or more nuclear localization sequences (NLSs), such as about or more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more NLSs. In certain embodiments, the second element comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 NLSs at or near the amine or carboxy terminus or a combination thereof. (eg one or more NLS at the amine end and one or more NLS at the carboxy end). When there are one or more NLSs, each NLS and other NLSs can be independently selected such that a single NLS can exist in more than one copy number and/or can exist with one or more others in one or more copies. NLSs are combined. A "guide sequence" is any polynucleotide sequence that is sufficiently complementary to a target polynucleotide sequence to hybridize to the target sequence and directs the Cas9 ribonucleoprotein to specifically bind to the sequence of the target sequence. Exemplary Cas9 proteins, plastids, and ribonucleoproteins are described in US 20140068797 (published March 6, 2014), US 2015031134 (published January 29, 2015), and US 2015079681 (published on March 19, 2015). The entire contents of these patent applications are hereby incorporated by reference in their entirety for all purposes.

於某些實施態樣中，該引導序列包含至少8個核苷 酸，其中當使用最適並列演算進行最佳並列時，該引導序列與彼之對應標的序列的互補程度為約或超過約50%、60%、75%、80%、85%、90%、95%、97.5%、99%或大於99%。使用供並列序列之任何最適演算可測定最佳並列，該最適演算之非限制性實例包括Smith-Waterman演算、Needleman-Wunsch演算、以Burrows-Wheeler轉換為基礎之演算(例如Burrows Wheeler並列)、ClustalW、Clustal X、BLAT、Novoalign(Novocraft Technologies,ELAND(Illumina,San Diego,Calif.))、SOAP(可得自網址soap.genomics.org.cn)及Maq(可得自網址maq.sourceforge.net)。In certain embodiments, the leader sequence comprises at least 8 nucleosides An acid, wherein when the optimal side-by-side calculus is used for optimal juxtaposition, the degree of complementation of the leader sequence with the corresponding target sequence is about or more than about 50%, 60%, 75%, 80%, 85%, 90%, 95 %, 97.5%, 99% or greater than 99%. The best juxtaposition can be determined using any optimal calculus for the parallel sequence, including non-limiting examples of Smith-Waterman calculus, Needleman-Wunsch calculus, Burrows-Wheeler-based calculus (eg, Burrows Wheeler juxtaposition), ClustalW , Clustal X, BLAT, Novoalign (Novocraft Technologies, ELAND (Illumina, San Diego, Calif.)), SOAP (available at the website soap.genomics.org.cn) and Maq (available at url maq.sourceforge.net) .

源自包括肺炎鏈球菌、釀膿鏈球菌及嗜熱鏈球菌之不同物種的Cas9蛋白序列具有保留之結構，該結構具有HNH復位核酸內切酶結構域和分離之RuvC/RNaseH核酸內切酶結構域，使得每個Cas9蛋白共有4個主要模體：模體1、2及4係似RuvC模體且模體3係HNH模體。對釀膿鏈球菌(SEQ ID No：8)，模體1係SEQ ID NO：260，模體2係SEQ ID NO：261，模體3係SEQ ID NO：262且模體4係SEQ ID NO：263。因此，“Cas9蛋白序列”意謂多肽，其包含具有至少4個模體之胺基酸序列，該4個模體與SEQ ID NO：260至263中任一者之該Cas9胺基酸序列的模體1、2、3及4或與於SEQ ID NO：1至829所示之胺基酸序列中任一者的對應部分具有至少約75%、至少約80%、至少約85%、至少約90%、至少約95%、至少約 99%或100%之胺基酸序列同一性。於另一實施態樣中，該Cas9胺基酸序列係與SEQ ID NO：8之位置7至166或731至1033的胺基酸或與SEQ ID NO：1至7和9至829所示之對應胺基酸具有至少約75%、至少約80%、至少約85%、至少約90%、至少約95%、至少約99%或100%之胺基酸序列同一性。The Cas9 protein sequence derived from different species including Streptococcus pneumoniae, Streptococcus pyogenes and Streptococcus thermophilus has a retained structure with a HNH reset endonuclease domain and an isolated RuvC/RNaseH endonuclease structure The domain has a total of four major motifs per Cas9 protein: motifs 1, 2 and 4 are like RuvC motifs and motif 3 is HNH motifs. For S. pyogenes (SEQ ID No: 8), phantom 1 is SEQ ID NO: 260, phantom 2 is SEQ ID NO: 261, phantom 3 is SEQ ID NO: 262 and motif 4 is SEQ ID NO: :263. Thus, "Cas9 protein sequence" means a polypeptide comprising an amino acid sequence having at least 4 motifs, and the 4 motifs of the Cas9 amino acid sequence of any one of SEQ ID NOs: 260 to 263 The motifs 1, 2, 3 and 4 or at least corresponding to any of the amino acid sequences set forth in SEQ ID NOS: 1 to 829 have at least about 75%, at least about 80%, at least about 85%, at least About 90%, at least about 95%, at least about 99% or 100% amino acid sequence identity. In another embodiment, the Cas9 amino acid sequence is linked to the amino acid of positions 7 to 166 or 731 to 1033 of SEQ ID NO: 8 or to SEQ ID NOS: 1 to 7 and 9 to 829. The corresponding amino acid has at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99% or 100% amino acid sequence identity.

該Cas9蛋白序列可經修飾，諸如經密碼子最佳化以表現於真核細胞，或該序列包括修飾以影響彼之功能。於某些實施態樣中，諸如使用Cas9切口酶(即Cas9-D10A)與引導序列(例如2個引導序列，其分別標靶DNA標的之意義股和反義股，因而使該2股皆產生切口而導致非同質終端接合)之組合，該Cas9蛋白序列指導於該標的序列之位置切割該DNA之1或2股。具有單一引導序列之Cas9-D10A可創造專一性序列***與刪除(indels)。然而，於其他實施態樣中，該Cas9蛋白序列缺少DNA股切割活性，諸如選擇性使用不具有催化活性之Cas(dCas)結構域。於其他實施態樣中，該Cas9蛋白序列係經修飾以共價連接該Cas9蛋白或Cas9核糖核蛋白，該修飾包括離胺酸和半胱胺酸殘基修飾。再於其他實施態樣中，該Cas9核糖核蛋白能指導切割RNA股(參閱文獻O/'Connell,Mitchell R.,et al.,Programmable RNA recognition and cleavage by CRISPR/Cas9,Nature,2014,516,p263-266)。The Cas9 protein sequence can be modified, such as by codon optimization to be expressed in eukaryotic cells, or the sequence includes modifications to affect its function. In certain embodiments, such as using a Cas9 nickase (ie, Cas9-D10A) and a leader sequence (eg, two leader sequences, which respectively target the sense strands of the DNA target and the antisense strands, thereby causing the two strands to be produced The combination of a nick that results in a non-homogeneous terminal junction, the Cas9 protein sequence directs the cleavage of one or two strands of the DNA at the position of the target sequence. Cas9-D10A with a single boot sequence creates unique sequence insertions and deletions (indels). However, in other embodiments, the Cas9 protein sequence lacks DNA strand cleavage activity, such as the selective use of a catalytically inactive Cas (dCas) domain. In other embodiments, the Cas9 protein sequence is modified to covalently link the Cas9 protein or Cas9 ribonucleoprotein, the modification comprising an amino acid and a cysteine residue modification. In still other embodiments, the Cas9 ribonucleoprotein is capable of directing cleavage of RNA strands (see O/'Connell, Mitchell R., et al., Programmable RNA recognition and cleavage by CRISPR/Cas9, Nature, 2014, 516, P263-266).

該Cas9蛋白序列之修飾可包括D10A(SEQ ID NO：8之胺基酸位置10的天冬胺酸為丙胺酸)突變(或SEQ ID NO：1至829所示之蛋白中任一者的對應之突變)，該突變可切割標的DNA之互補股但切割標的DNA之非互補股的能力降低(因此導致單股斷裂而非雙股斷裂)。另一修飾係H840A(SEQ ID NO：8之胺基酸位置840的組胺酸為丙胺酸)突變(或SEQ ID NO：1至829所示之蛋白中任一者的對應之突變)，該突變可切割標的DNA之非互補股但切割標的DNA之互補股的能力降低(因此導致單股斷裂而非雙股斷裂)。使用Cas9之D10A或H840A變異體(或SEQ ID NO：1至829所示之蛋白中任一者的對應之突變)可改變預期之生物性結果，因為當雙股斷裂而非單股斷裂存在時，非同一性終端連接更可能會發生。Modification of the Cas9 protein sequence may include D10A (aspartic acid of position 10 of the amino acid of SEQ ID NO: 8 is alanine) mutation (or SEQ ID) NO: the corresponding mutation of any of the proteins shown in 1 to 829), which cleaves the complementary strand of the target DNA but reduces the ability of the non-complementary strand of the target DNA to be reduced (thus resulting in a single strand break rather than a double strand break) ). Another modification is a mutation in H840A (a histidine acid of amino acid position 840 of SEQ ID NO: 8 is alanine) (or a corresponding mutation of any of the proteins shown in SEQ ID NOS: 1 to 829), Mutations can cleave non-complementary strands of the target DNA but reduce the ability to cleave the complementary strands of the target DNA (thus resulting in a single strand break rather than a double strand break). Use of the D10A or H840A variant of Cas9 (or the corresponding mutation of any of the proteins shown in SEQ ID NOS: 1 to 829) can alter the expected biological result, as a double strand break rather than a single strand break exists Non-identity terminal connections are more likely to occur.

其他殘基可經突變以使源自模體1、2、3或4之特定核酸酶亦失去活性。作為非限制性實例，殘基D10、G12、G17、E762、H840、N854、N863、H982、H983、A984、D986及/或A987(或SEQ ID NO：1至829所示之蛋白中任一者的對應之突變)可經突變。突變可包括取代、加入及刪除、或彼等之任何組合。於某些情況下，突變將被突變之胺基酸轉化為另一胺基酸，諸如丙胺酸。其他修飾包括鹼基修飾、骨架修飾及/或核苷間連結修飾。Other residues may be mutated such that the particular nuclease derived from motif 1, 2, 3 or 4 is also inactivated. By way of non-limiting example, any of the residues D10, G12, G17, E762, H840, N854, N863, H982, H983, A984, D986 and/or A987 (or the proteins shown in SEQ ID NOS: 1 to 829) The corresponding mutation) can be mutated. Mutations can include substitutions, additions and deletions, or any combination thereof. In some cases, the mutation converts the mutated amino acid to another amino acid, such as alanine. Other modifications include base modifications, backbone modifications, and/or internucleoside linkage modifications.

“核定位序列”(NLS)意謂幫助Cas9核糖核蛋白進入真核細胞之細胞核的胺基酸序列。於是，NLS典型上包含暴露於該蛋白表面之帶正電荷的離胺酸或精胺酸之一或多個短序列。NLS之實例包括但不限於衍生自下述之NLS序列：SV40病毒大T抗原之具有胺基酸序列PKKKRKV (SEQ ID NO：830)之NLS；源自核胞漿素之NLS(例如具有胺基酸序列KRPAATKKAGQAKKKK(SEQ ID NO：831)之核胞漿素二部NLS)；具有胺基酸序列PAAKRVKLD(SEQ ID NO：832)或RQRRNELKRSP(SEQ ID NO：833)之c-myc NLS；具有胺基酸序列NQSSNFGPMKGGNFGGRSSGPYGGGGQYFAKPRNQGGY(SEQ ID NO：834)之hRNPA1 M9 NLS；源自胞核內輸蛋白α之IBB結構域的胺基酸序列RMRIZFKNKGKDTAELRRRRVEVSVELRKAKKDEQILKRRNV(SEQ ID NO：835)；肌瘤T蛋白之胺基酸序列VSRKRPRP(SEQ ID NO：836)和PPKKARED(SEQ ID NO：837)；人p53之胺基酸序列PQPKKKPL(SEQ ID NO：838)；鼠c-abl IV之胺基酸序列SALIKKKKKMAP(SEQ ID NO：839)；流感病毒NS1之胺基酸序列DRLRR(SEQ ID NO：840)和PKQKKRK(SEQ ID NO：841)；肝炎病毒δ抗原之胺基酸序列RKLKKKIKKL(SEQ ID NO：842)；鼠Mx1蛋白之胺基酸序列REKKKFLKRR(SEQ ID NO：843)；人聚(ADP核糖)聚合酶之胺基酸序列KRKGDEVDGVDEVAKKKSKK(SEQ ID NO：844)；(人)糖皮質激素之類固醇激素受體的胺基酸序列RKCLQAGMNLEARKTKK(SEQ ID NO：845)；胺基酸序列MAPKKKRKVGIHRGVP(SEQ ID NO：846)；及，胺基酸序列PKKKRKVEDPKKKRKVD(SEQ ID NO：847)。"Nuclear localization sequence" (NLS) means an amino acid sequence that facilitates entry of Cas9 ribonucleoprotein into the nucleus of eukaryotic cells. Thus, NLS typically comprises one or more short sequences of a positively charged lysine or arginine exposed to the surface of the protein. Examples of NLS include, but are not limited to, NLS sequences derived from the SV40 viral large T antigen having the amino acid sequence PKKKRKV NLS of (SEQ ID NO: 830); NLS derived from nuclear cytoplasmin (eg, nuclear cytosolic two-part NLS having the amino acid sequence KRPAATKKAGQAKKKK (SEQ ID NO: 831); having the amino acid sequence PAAKRVKLD ( SEQ ID NO: 832) or c-myc NLS of RQRRNELKRSP (SEQ ID NO: 833); hRNPA1 M9 NLS having amino acid sequence NQSSNFGPMKGGNFGGRSSGPYGGGGQYFAKPRNQGGY (SEQ ID NO: 834); IBB structure derived from intranuclear transfer protein alpha The amino acid sequence of the domain RMRIZFKNKGKDTAELRRRRVEVSVELRKAKKDEQILKRRNV (SEQ ID NO: 835); the amino acid sequence of the fibroid T protein VSRKRPRP (SEQ ID NO: 836) and PPKKARED (SEQ ID NO: 837); the amino acid sequence of human p53 PQPKKKPL (SEQ ID NO: 838); Amino acid sequence SALIKKKKKMAP (SEQ ID NO: 839) of murine c-abl IV; amino acid sequence DRLRR (SEQ ID NO: 840) and PKQKKRK (SEQ ID NO:) of influenza virus NS1 841); amino acid sequence of hepatitis A δ antigen RKLKKKIKKL (SEQ ID NO: 842); amino acid sequence of murine Mx1 protein REKKKFLKRR (SEQ ID NO: 843); amino acid of human poly(ADP ribose) polymerase The sequence KRKGDEVDGVDEVAKKKSKK (SEQ ID NO: 844); the amino group of the steroid hormone receptor (human) glucocorticoid Sequence RKCLQAGMNLEARKTKK (SEQ ID NO: 845); amino acid sequence MAPKKKRKVGIHRGVP (SEQ ID NO: 846); and, the amino acid sequence PKKKRKVEDPKKKRKVD (SEQ ID NO: 847).

於式(A)化合物之一實施態樣中，R1 係Z-X-Y且R2 係 -NH-C(O)-CH3 。In one embodiment of the compound of formula (A), R 1 is ZXY and R 2 is -NH-C(O)-CH 3 .

於式(A)化合物之另一實施態樣中，Y係RNA序列。In another embodiment of the compound of formula (A), the Y-line RNA sequence.

再於式(A)化合物之另一實施態樣中，Y係siRNA序列。In another embodiment of the compound of formula (A), a Y-line siRNA sequence.

於另一實施態樣中，式(A)化合物能與存在於肝細胞上之受體結合。In another embodiment, the compound of formula (A) is capable of binding to a receptor present on hepatocytes.

於另一實施態樣中，存在於肝細胞上之受體係去唾液酸糖蛋白受體。In another embodiment, the systemic asialoglycoprotein receptor is present on hepatocytes.

於醫藥組成物之一實施態樣中，該化合物或彼之治療上可接受之鹽係以治療有效量存在。In one embodiment of the pharmaceutical composition, the compound or a therapeutically acceptable salt thereof is present in a therapeutically effective amount.

本發明之化合物可藉由合成途徑合成，該合成途徑包括類似於化學技術所習知之方法，特別是本發明所包含之方法。起始物通常可得自於商業來源，諸如Aldrich Chemicals(Milwaukee,WI)，或藉由使用熟習此技術之人士所習知的方法輕易地製備(例如藉由文獻Louis F.Fieser and Mary Fieser,Reagents for Organic Synthesis,v.1-19,Wiley,New York(1967-1999版)或Beilsteins Handbuch der organischen Chemie,4,Aufl.ed.Springer-Verlag,Berlin，其包括補充集(亦可得自於Beilstein線上資料庫)所一般描述之方法製備)。The compounds of the present invention can be synthesized by synthetic routes including those well known in the art of chemical engineering, particularly the methods encompassed by the present invention. The starting materials are typically available from commercial sources, such as Aldrich Chemicals (Milwaukee, WI), or are readily prepared by methods known to those skilled in the art (e.g., by the literature by Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, New York (1967-1999 edition) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, which includes supplemental sets (also available from Beilstein online database) prepared by the method generally described).

為說明目的，下述說明之反應圖提供合成本發明之化合物的可能途徑及主要合成中間體。對於個別反應步驟之更為詳細的說明，參閱下述之實施方式乙節。熟習此技術之人士當能瞭解可使用其他合成途徑以合成本發明之化合 物。雖然特定之起始物和反應劑係示於該等反應圖且說明如下，但是其他起始物和反應劑可經易地替代以提供各種不同之衍生物類及/或反應條件。此外，依據本發明之揭露，使用熟習此技術之人士所習知的一般化學，藉由下述方法所製備之許多化合物可經進一步修飾。For illustrative purposes, the reaction schemes described below provide possible pathways for the synthesis of the compounds of the invention and the major synthetic intermediates. For a more detailed description of the individual reaction steps, see Section VIII of the following. Those skilled in the art will recognize that other synthetic routes can be used to synthesize the compounds of the present invention. Things. While specific starting materials and reactants are shown in the schemes and are illustrated below, other starting materials and reactants can be readily substituted to provide a variety of different derivatives and/or reaction conditions. Moreover, many of the compounds prepared by the methods described below can be further modified in accordance with the teachings of the present invention using the general chemistry known to those skilled in the art.

於製備本發明之化合物中，保護中間體之遠端官能基(例如一級或二級胺)可能是必要的。取決於遠端官能基之本性和製備方法之條件，該保護需要可加以變化。適當之胺基保護基(NH-Pg或NPg)包括乙醯基、三氟乙醯基、三級丁氧羰基(BOC)、苄氧羰基(CBz)、9-茀基甲氧羰基(Fmoc)及酞醯亞胺(Pht)。“羥基保護基”係指羥基之取代基，該取代基阻斷或保護羥基官能性。適當之羥基保護基(O-Pg)包括例如烯丙基、乙醯基(Ac)、矽基(如三甲基矽基(TMS)或三級丁基二甲基矽基(TBS))、苄基(Bn)、對甲氧基苄基(PMB)、三苯甲基(Tr)、對溴苄醯基、對硝基苯醯基及類似基(用於保護1,2-或1,3-二醇之亞苄基、環縮酮、鄰酯及鄰醯胺)。熟習此技術之人士可輕易地決定該保護需要。對於保護基和彼等之用途的一般描述，參閱文獻T.W.Greene,Protective Groups in Organic Synthesis,John Wiley & Sons,New York,1991。In preparing the compounds of the invention, it may be necessary to protect the distal functional groups of the intermediate (e.g., primary or secondary amines). This protection needs to be varied depending on the nature of the remote functional group and the conditions of the preparation process. Suitable amine protecting groups (NH-Pg or NPg) include ethenyl, trifluoroethenyl, tertiary butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), 9-fluorenylmethoxycarbonyl (Fmoc) And quinone imine (Pht). "Hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable hydroxy protecting groups (O-Pg) include, for example, allyl, ethyl (Ac), sulfhydryl (such as trimethylsulfonyl (TMS) or tert-butyl dimethyl fluorenyl (TBS)), Benzyl (Bn), p-methoxybenzyl (PMB), trityl (Tr), p-bromobenzyl, p-nitrophenyl fluorenyl and the like (for protecting 1, 2 or 1, a benzylidene group of 3-diol, a cyclic ketal, an orthoester, and an o-amine. Those skilled in the art can easily determine this protection need. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

反應圖1說明可用於提供本發明之化合物的一般方法。於反應圖1之步驟1中，可藉由文獻H.Paulsen and M.Paal in Carbohydrate Research,135,53(1984)描述之方法所製備的合成中間體(I-a)於慣用之條件下[於室溫(約23 ℃)下使用三甲基矽基氯和吡啶]並隨後令保護一級醇之該三甲基矽基經選擇性切除(於約-10℃至室溫之溫度下、於醇溶劑(諸如甲醇)中及於鹼性條件(諸如碳酸鉀)下進行反應)而經全矽烷化以顯示一級醇中間體(I-b)。於反應圖1之步驟2中，藉由文獻J.R.Parikh and William v.E.Doering,Journal of the American Chemical Society,89,5505-5507(1967)所描述之Parikh-Doering氧化反應，可將中間體(I-c)之額外羥基伸甲基導入至糖苷，隨後於約室溫至約60℃之溫度下、於水或醇溶劑中及於鹼金屬氫氧化物(例如氫氧化鈉或烷氧化鈉)之存在下，進行與甲醛來源(例如甲醛水溶液或聚甲醛固體)之反應。此反應稱為醛醇-Cannizzaro反應。亦可使用熟習此技術之人士所習知的該方法之修飾者。例如，亦可使用其他氧化劑，諸如文獻Ozanne,A.et al.,Organic Letters,5,2903(2003)所描述之經安定化的2-碘醯基苯甲酸、文獻Kanji Omura and Daniel Swern,Tetrahedron,34,1651(1978)所描述之Swern氧化反應及熟習此技術之人士所習知的其他氧化劑。該醛醇-Cannizzaro順序業已描述於文獻Robert Schaffer,Journal of The American Chemical Society,81,5452(1959)和Amigues,E.J.,et al.,Tetrahedron,63,10042(2007)。反應圖1之步驟2的實驗條件亦促進保護二級醇之該三甲基矽基的切割。於反應圖1之步驟3中，於約室溫至約100℃之溫度下且於溶劑(諸如水)中，令中間體(I-c)與有機酸或無機酸(例如硫酸)或酸性樹脂反應以 生成本發明之化合物(1)。於反應圖1之步驟4中，化合物(1)可與已知能還原疊氮基至對應之胺的還原劑反應(例如過渡金屬媒介之催化氫化反應，於熟習此技術之人士所習知的慣用之實驗條件下使用三苯膦水溶液)。隨後於乙醯化劑(例如乙酸酐或乙醯氯；於0至80℃之溫度下、於吡啶或三乙胺之存在下及於溶劑(諸如二氯甲烷或四氫呋喃)中)之存在下進行反應以生成本發明之化合物(2)。於反應圖1之步驟5中，於約0℃至室溫之溫度下、於溶劑或多種溶劑之混合物(諸如醇溶劑或四氫呋喃)中及於烷氧化物(例如甲氧化鈉)之存在下，令化合物(2)進行反應以生成本發明之化合物(3)。進一步，藉由使用熟習此技術之人士所習知的保護基和官能基操作順序，所得之化合物可隨後輕易地經官能化以生成本發明所請之其他化合物。因此，於反應圖1之步驟6和7中，化合物(1)和(3)之二級羥基可分別藉由適當之保護基經進一步保護(例如於約室溫至約90℃之溫度下、於溶劑(諸如N,N-二甲基甲醯胺)中及於酸性條件下，經與2,2-二甲氧基丙烷反應以生成環狀縮酮)以形成中間體，諸如中間體(I-d)和中間體(I-e)。再者，藉由使用熟習此技術之人士所習知的合成轉換及官能基和保護基操作，中間體(I-d)和中間體(I-e)經一級羥基之進一步官能化和衍生化以連結所欲之連接子X和配體Y以生成本發明所請之含有該XY之化合物。藉由使用熟習此技術之人士所習知的反應劑和條件(例如於2個Pg形成環狀縮酮(諸如縮丙酮化合物)之情況下，於室溫至約80℃ 之溫度下，於溶劑或多種溶劑之混合物(諸如乙酸、醇溶劑、水或四氫呋喃)中及於使用酸(諸如乙酸)之酸性條件下，可除去該Pg)，除去保護基(例如Pg)以生成二級羥基且進而生成本發明所請之含有該XY之化合物。例如，經保護基操作和去除後，中間體(I-e)之一級羥基經烷基化可生成本發明所請之對應醚連結的含有該XY之化合物。藉由使用熟習此技術之人士所習知的適當反應物和反應劑，自化合物(3)或中間體(I-e)亦可方便地生成本發明所請之酯連結、碳酸酯連結或胺甲酸酯連結的含有該XY之化合物。經保護基操作和去除後，轉化中間體(I-e)之一級羥基為對應之三氟甲磺酸酯(III-e-1)並隨後經適當之親核劑進行親核性替代反應可生成本發明所請之對應醚連結和硫醚連結的含有該XY之化合物。該硫醚中間體之氧化亦可生成本發明所請之對應亞碸連結和碸連結的含有該XY之化合物。此外，化合物(III-e-1)之一級三氟甲磺酸酯經硫代乙酸鉀替代並隨後經硫酯水解可生成對應之硫醇(III-e-2)，該硫醇經保護基操作和去除後生成本發明之化合物(IV-e-1)；該硫醇(III-e-2)經進一步烷基化且經保護基操作和去除後亦可生成本發明所請之硫醚連結的含有該XY之化合物。硫醇(III-e-2)亦可被轉化為對應之磺醯氯且與適當之胺反應且經保護基操作和去除後生成本發明之磺醯胺連結的含有該XY之化合物。一級三氟甲磺酸酯(III-e-1)經疊氮化鈉替代亦可生成對應之含有疊氮化物的化合物(III-e-3)，其係經保護基操作和去除後生成本發明之化合 物(IV-e-2)。還原化合物(III-e-3)可生成對應之一級胺(III-e-4)，其係經進一步官能化(例如醯胺鍵生成、還原性胺化反應、磺醯胺生成、脲生成、胺甲酸酯生成等)以連結該XY取代基且經保護基操作和去除後生成本發明所請之化合物。經保護基操作和去除後，化合物(III-e-4)亦可生成本發明之化合物(IV-e-3)。上述疊氮化物中間體(III-e-3)與含有炔或腈之反應劑或合成中間體反應並隨後於熟習此技術之人士所習知的條件下進行保護基操作和去除，亦可分別生成本發明所請之***連結或四唑連結的含有該XY之化合物。氧化化合物(I-e)之一級羥基成對應之醛(III-e-5)並隨後於熟習此技術之人士所習知的慣用條件下使用適當之胺進行還原性胺化反應，或烯烴化反應(諸如Wittig型、Horner-Wadsworth-Emmons型、Petterson型、Julia型及彼等之修飾型)並隨後還原所生成之烯烴(使用例如熟習此技術之人士所習知的金屬媒介之催化氫化反應或二醯胺媒介之還原反應)且分別經官能基操作及保護基操作和去除後，可生成本發明所請之所欲氮連結或碳連結的含有該XY之化合物。轉化醛(III-e-5)為對應之炔(III-e-6)(使用Corey-Fuchs型反應或使用Seyferth-Gilbert型反應劑)且隨後經保護基操作和去除後，可生成本發明所請之化合物(IV-e-4)。再者，炔(III-e-6)或化合物(IV-e-4)與含有疊氮化物之反應劑或合成中間體反應並隨後於熟習此技術之人士所習知的條件下進行保護基操作和去除，亦可生成本發明所請之***連結的含有該XY之化合物。於熟習此技 術之人士所習知的金屬媒介之交叉偶合反應(諸如Sonogashira型反應)下，經與適當之反應劑反應，炔(III-e-6)亦可作為有用之合成中間體以生成本發明所請之其他化合物。使用熟習此技術之人士所習知的合成轉換方法，氧化化合物(I-e)之一級羥基為對應之酸(III-e-7)且經保護基去除後，生成本發明所請之酯連結和醯胺連結的含有該XY之化合物。化合物(III-e-7)之保護基操作和去除亦提供生成本發明之化合物(IV-e-5)的方法。於熟習此技術之人士所習知的條件下，轉化化合物(IV-e-5)或化合物(III-e-7)為對應之一級醯胺直接生成本發明所請之化合物(IV-e-6)或化合物(III-e-8)，該化合物(III-e-8)經保護基操作和去除後生成化合物(IV-e-6)。此外，化合物(III-e-8)之醯胺官能基的脫水可生成對應之腈(III-e-9)，其係經官能基操作和去除後生成本發明之化合物(IV-e-7)。一級三氟甲磺酸酯(III-e-1)經氰化物離子置換亦可生成對應之含有腈之化合物(III-e-10)，其係經保護基操作和去除後生成本發明之化合物(IV-e-8)。再者，化合物(IV-e-8)或化合物(III-e-10)之腈的水解可直接提供生成酸(IV-e-9)或化合物(III-e-11)之方法，該化合物(III-e-11)經保護基操作和去除後生成化合物(IV-e-9)。含有炔之化合物(諸如化合物(III-e-6)/化合物(IV-e-4))、含有一級醯胺之化合物(諸如化合物(III-e-8)/化合物(IV-e-6))、含有腈之化合物(諸如化合物(III-e-9)/化合物(IV-e-7)/化合物(III-e-10)/化合物(IV-e-8))、含有酸之化合物(諸如化合物(III-e-7)/化合物(IV-e-5)/化合物(III-e- 11)/化合物(IV-e-9))及含有醛之化合物(諸如化合物(III-e-5))亦可進一步經官能化且亦可進一步於熟習此技術之人士所習知的條件下與適當之反應劑和合成中間體反應(參閱文獻J.A.Joule and K.Mills,Heterocyclic Chemistry,第5版，Wiley Ed.,(2010)；J.J.Li,Name Reactions in heterocyclic chemistry,Wiley,(2005)；M.R.Grimmett Advances in Heterocyclic Chemistry,27,241,(1981)；I.G.Turchi et al.,Chemical Reviews,75,389,(1975)；K.T.Potts,Chemical Reviews,61,87,(1961)；R.H.Wiley,Organic Reactions,6,367,(1951)；L.B.Clapp,Advances in Heterocyclic Chemistry,20,65,(1976)；A.Hetzheim et al.,Advances in Heterocyclic Chemistry,7,183,(1967)；J.Sandstrom,Advances in Heterocyclic Chemistry,9,165,(1968)；S.J.Wittenberger,Organic Preparations and Procedures International,26,499,(1994)；M.G.Finn et al.,Angewandte Chemie International Edition,48,9879,(2009))以生成本案所請之額外的5和6員環(諸如異噁唑、異噻唑、吡唑、噁唑、噻唑、咪唑、1,2,4-噁二唑、1,2,4-噻二唑、1,2,4-***、1,3,4-噁二唑、1,3,4-噻二唑、四唑及1,2,3-***)連結之含有該XY之化合物。經由熟習此技術之人士所習知的苯環化反應(諸如Danheiser型或Dotz型苯環化反應)，自炔(諸如化合物(III-e-6)和化合物(IV-e-4))或該等炔之經雜取代的類似物(即化合物(III-e-6)/化合物(IV-e-4)之炔氫經OR4 、N(R4 )2 或SR4 替代；使用 熟習此技術之人士所習知的條件和反應劑可生成該等化合物)，亦可生成本案所請之芳基環連結的含有該XY之化合物。Scheme 1 illustrates a general method that can be used to provide a compound of the invention. In the first step of the reaction scheme of Figure 1, the synthetic intermediate (Ia) prepared by the method described in the literature by H. Paulsen and M. Paal in Carbohydrate Research, 135, 53 (1984) can be used under conventional conditions. The trimethylsulfonyl chloride and pyridine are used at a temperature (about 23 ° C) and then the trimethylsulfonyl group protecting the primary alcohol is selectively excised (at a temperature of about -10 ° C to room temperature in an alcohol solvent). The reaction is carried out in (such as methanol) under basic conditions (such as potassium carbonate) and is fully decylated to give the primary alcohol intermediate (Ib). In step 2 of Reaction Scheme 1, an additional intermediate (Ic) can be obtained by the Parikh-Doering oxidation reaction described in JRParikh and William vEDoering, Journal of the American Chemical Society, 89, 5505-5507 (1967). The hydroxymethyl group is introduced into the glycoside, followed by the reaction at a temperature of from about room temperature to about 60 ° C in water or an alcohol solvent and in the presence of an alkali metal hydroxide such as sodium hydroxide or sodium alkoxide. The reaction of a source of formaldehyde, such as aqueous formaldehyde or polyoxymethylene solids. This reaction is called the aldol-Cannizzaro reaction. Modifiers of the method known to those skilled in the art can also be used. For example, other oxidizing agents may also be used, such as the stabilized 2-iododecylbenzoic acid described in the literature by Ozanne, A. et al., Organic Letters, 5, 2903 (2003), literature Kanji Omura and Daniel Swern, Tetrahedron The Swern oxidation reaction described in 34, 1651 (1978) and other oxidants known to those skilled in the art. This aldol-Cannizzaro sequence has been described in the literature by Robert Schaffer, Journal of The American Chemical Society, 81, 5452 (1959) and Amigues, EJ, et al., Tetrahedron, 63, 10042 (2007). The experimental conditions of step 2 of Reaction Scheme 1 also promote the protection of the trimethylsulfonyl group of the secondary alcohol. In step 3 of Reaction Scheme 1, the intermediate (Ic) is reacted with an organic or inorganic acid (such as sulfuric acid) or an acidic resin at a temperature of from about room temperature to about 100 ° C in a solvent such as water. The compound (1) of the present invention is produced. In step 4 of Reaction Scheme 1, compound (1) can be reacted with a reducing agent known to reduce the azide group to the corresponding amine (e.g., catalytic hydrogenation of a transition metal medium, as is customary to those skilled in the art). An aqueous solution of triphenylphosphine was used under the experimental conditions. Subsequent to the presence of an oxime (for example acetic anhydride or acetamidine; in the presence of pyridine or triethylamine in a solvent such as dichloromethane or tetrahydrofuran at a temperature of from 0 to 80 ° C) The reaction is carried out to give the compound (2) of the present invention. In the step 5 of the reaction scheme of Figure 1, in the presence of a solvent or a mixture of solvents (such as an alcohol solvent or tetrahydrofuran) and alkoxide (such as sodium methoxide) at a temperature of about 0 ° C to room temperature, Compound (2) is allowed to react to form compound (3) of the present invention. Further, the resulting compounds can then be readily functionalized to form other compounds of the present invention by using the protecting groups and functional group manipulation sequences known to those skilled in the art. Thus, in steps 6 and 7 of Reaction Scheme 1, the secondary hydroxyl groups of compounds (1) and (3) can be further protected by a suitable protecting group, respectively (for example, at a temperature of from about room temperature to about 90 ° C, Forming an intermediate, such as an intermediate, in a solvent such as N,N-dimethylformamide under acidic conditions by reaction with 2,2-dimethoxypropane to form a cyclic ketal) Id) and intermediate (Ie). Furthermore, intermediates (Id) and intermediates (Ie) are further functionalized and derivatized by a primary hydroxyl group to link as desired by synthetic conversion and functional group and protecting group procedures well known to those skilled in the art. The linker X and the ligand Y are used to form the compound containing the XY as claimed in the present invention. By using reagents and conditions well known to those skilled in the art (for example, in the case of 2 Pg forming a cyclic ketal (such as a acetal compound), at a temperature of from room temperature to about 80 ° C in a solvent Or a mixture of a plurality of solvents (such as acetic acid, an alcohol solvent, water or tetrahydrofuran) and under acidic conditions using an acid such as acetic acid, the Pg may be removed, and a protecting group (for example, Pg) may be removed to form a secondary hydroxyl group and further The compound containing the XY requested by the present invention is produced. For example, after manipulation and removal by a protecting group, the alkyl group of one of the intermediate (Ie) is alkylated to form the corresponding ether-linked compound containing the XY of the present invention. Ester linkages, carbonate linkages or urethanes of the present invention may also be conveniently formed from compound (3) or intermediate (Ie) by the use of suitable reactants and reactants known to those skilled in the art. The ester-linked compound containing the XY. After manipulation and removal by a protecting group, the primary hydroxyl group of the intermediate (Ie) is converted to the corresponding triflate (III-e-1) and then subjected to a nucleophilic substitution reaction by a suitable nucleophile to form a product. The compound containing the XY corresponding to the ether linkage and the thioether is required for the invention. Oxidation of the thioether intermediate can also produce a compound containing the XY corresponding to the desired hydrazine linkage and hydrazine linkage of the present invention. Further, the one-stage trifluoromethanesulfonate of the compound (III-e-1) is replaced by potassium thioacetate and subsequently hydrolyzed by a thioester to form a corresponding thiol (III-e-2) having a protecting group. After operation and removal, the compound (IV-e-1) of the present invention is produced; the thiol (III-e-2) can be further alkylated and subjected to protection and removal to form the desired thioether of the present invention. A linked compound containing the XY. The thiol (III-e-2) can also be converted to the corresponding sulfonium chloride and reacted with a suitable amine and treated and removed by a protecting group to form a sulfonamide-linked compound containing the XY of the present invention. The primary triflate (III-e-1) can also be substituted with sodium azide to form the corresponding azide-containing compound (III-e-3), which is protected and manipulated to form Inventive compound (IV-e-2). Reduction of compound (III-e-3) produces the corresponding mono-amine (III-e-4) which is further functionalized (eg, guanamine bond formation, reductive amination, sulfonamide formation, urea formation, The urethane formation, etc.), by linking the XY substituents and operating and removing them with a protecting group, produces the compounds of the present invention. Compound (III-e-4) can also form the compound (IV-e-3) of the present invention after being subjected to protection and removal. The azide intermediate (III-e-3) is reacted with a reagent or synthetic intermediate containing an alkyne or nitrile and subsequently subjected to protecting group operation and removal under conditions well known to those skilled in the art, or separately The triazole-linked or tetrazole-linked compound containing the XY of the present invention is produced. The hydroxy group of the compound (Ie) is oxidized to the corresponding aldehyde (III-e-5) and subsequently subjected to a reductive amination reaction or an olefination reaction using a suitable amine under the customary conditions known to those skilled in the art. Such as Wittig type, Horner-Wadsworth-Emmons type, Petterson type, Julia type and their modifications) and subsequent reduction of the resulting olefins (using a catalytic hydrogenation reaction or a metal medium known to those skilled in the art) The XY-containing compound can be formed by the functional group manipulation and the protective group operation and removal, respectively, to form the desired nitrogen-bonded or carbon-linked desired compound of the present invention. The present invention can be produced by converting the aldehyde (III-e-5) to the corresponding alkyne (III-e-6) (using a Corey-Fuchs type reaction or using a Seyferth-Gilbert type reactant) and then operating and removing it with a protecting group. The compound (IV-e-4) is requested. Further, the alkyne (III-e-6) or the compound (IV-e-4) is reacted with an azide-containing reactant or a synthetic intermediate and then subjected to a protecting group under conditions well known to those skilled in the art. The XY-containing compound linked to the triazole of the present invention can also be produced and removed. The alkyne (III-e-6) can also be used as a useful synthetic intermediate in the cross-coupling reaction of a metal medium known by those skilled in the art (such as a Sonogashira type reaction) by reaction with a suitable reactant. Cost other compounds requested by the invention. By using a synthetic conversion method known to those skilled in the art, the hydroxy group of the compound (Ie) is oxidized to the corresponding acid (III-e-7) and removed by a protecting group to form the desired ester linkage and hydrazine of the present invention. Amine-linked compound containing the XY. The protecting group manipulation and removal of the compound (III-e-7) also provides a method of producing the compound (IV-e-5) of the present invention. The compound (IV-e-5) or the compound (III-e-7) is converted to a corresponding one-stage guanamine to directly form the compound of the present invention (IV-e-) under conditions well known to those skilled in the art. 6) or the compound (III-e-8), which is subjected to manipulation and removal by a protecting group to give the compound (IV-e-6). Further, dehydration of the indoleamine functional group of the compound (III-e-8) can produce the corresponding nitrile (III-e-9) which is subjected to functional group operation and removal to form a compound of the present invention (IV-e-7) ). The first-stage trifluoromethanesulfonate (III-e-1) can also be substituted with a cyanide ion to form a corresponding nitrile-containing compound (III-e-10) which is subjected to manipulation and removal to form a compound of the present invention. (IV-e-8). Further, the hydrolysis of the nitrile of the compound (IV-e-8) or the compound (III-e-10) directly provides a method of producing an acid (IV-e-9) or a compound (III-e-11), which is a compound (III-e-11) The compound (IV-e-9) is produced after being protected and removed by a protecting group. a compound containing an alkyne such as the compound (III-e-6) / compound (IV-e-4), a compound containing a primary guanamine such as the compound (III-e-8) / compound (IV-e-6) a compound containing a nitrile such as a compound (III-e-9) / a compound (IV-e-7) / a compound (III-e-10) / a compound (IV-e-8), an acid-containing compound ( For example, the compound (III-e-7) / the compound (IV-e-5) / the compound (III-e-11) / the compound (IV-e-9)) and the compound containing an aldehyde (such as the compound (III-e-) 5)) may further be functionalized and may be further reacted with suitable reactants and synthetic intermediates under conditions well known to those skilled in the art (see JA Joule and K. Mills, Heterocyclic Chemistry, 5th edition). , Wiley Ed., (2010); JJLi, Name Reactions in heterocyclic chemistry, Wiley, (2005); MRGrimmett Advances in Heterocyclic Chemistry, 27, 241, (1981); IGTurchi et al., Chemical Reviews, 75, 389, (1975); KTPotts , Chemical Reviews, 61, 87, (1961); RH Wiley, Organic Reactions, 6, 367, (1951); LBClapp, Advances in Heterocyclic Chemistry, 20, 65, (1976); A. Hetzheim et al., Advances in Heterocyclic Chemistry, 7,183, (1 967); J. Sandstrom, Advances in Heterocyclic Chemistry, 9, 165, (1968); SJ Wittenberger, Organic Preparations and Procedures International, 26, 499, (1994); MG Finn et al., Angewandte Chemie International Edition, 48, 9879, (2009)) To generate additional 5 and 6 membered rings (such as isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, 1,2,4-oxadiazole, 1,2,4-thiadipine) a compound containing the XY, an azole, a 1,2,4-triazole, a 1,3,4-oxadiazole, a 1,3,4-thiadiazole, a tetrazole, and a 1,2,3-triazole) . a benzene cyclization reaction (such as a Danheiser type or a Dotz type benzene cyclization reaction) known to those skilled in the art, from alkyne (such as compound (III-e-6) and compound (IV-e-4)) or The hetero-substituted analog of the alkyne (ie, the alkyne hydrogen of the compound (III-e-6)/compound (IV-e-4) is replaced by OR 4 , N(R 4 ) 2 or SR 4 ; The conditions and reagents known to those skilled in the art can produce such compounds), and the XY-containing compounds linked by the aryl ring of the present invention can also be formed.

針對化合物(3)和化合物(I-e)之如上述類似的化學亦可應用於化合物(1)和中間體(I-d)以生成本案所請之額外化合物。進一步細節參閱下述之實施例。The chemistry similar to the above for the compound (3) and the compound (I-e) can also be applied to the compound (1) and the intermediate (I-d) to form the additional compound claimed herein. See the examples below for further details.

於反應圖1之步驟4中，使用三氟乙酸酐亦可提供生成N-((1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)-2,2,2-三氟乙醯胺(本發明之化合物(24))之方法。In step 4 of Reaction Scheme 1, the use of trifluoroacetic anhydride can also provide the formation of N-((1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6, Process for 8-dioxabicyclo[3.2.1]oct-4-yl)-2,2,2-trifluoroacetamide (compound (24) of the present invention).

可替代地，藉由反應圖2所描述之順序，可製備本發明之化合物(諸如化合物(3))。因此，2-乙醯胺基-2-去氧-α-D-半乳哌喃糖苷甲酯(II-a)可經氧化/Aldo-Cannizzaro反 應(類似於文獻A.W.Mazur,EP0341062(1989)，業已描述者)以生成中間體(II-b)。於上述和熟習此技術之人士所習知的條件下，經反應圖1之步驟3(橋連縮酮生成)、步驟4(乙醯化反應)及步驟5(酯水解反應)使化合物(II-b)進行反應以生成化合物(3)。使用反應圖2所描述之相同方法，自化合物(I-a)(或彼於變旋異構位置之表異構物)亦可生成化合物(1)。Alternatively, a compound of the invention (such as compound (3)) can be prepared by the sequence described in the reaction scheme of Figure 2. Thus, 2-ethylamido-2-deoxy-α-D-galactofuranoside methyl ester (II-a) can be oxidized/Aldo-Cannizzaro It should be (similar to the literature A.W. Mazur, EP 0341062 (1989), already described) to produce intermediate (II-b). Compounds (II) are prepared by the reaction of Step 3 (bridged ketal formation), Step 4 (acetylation reaction) and Step 5 (ester hydrolysis reaction) of Figure 1 in the above-described conditions well known to those skilled in the art. -b) The reaction is carried out to give the compound (3). Compound (1) can also be produced from compound (I-a) (or an epimer thereof which is in the position of a racemic isoform) by the same method as described in Reaction Scheme 2.

特別地，當R1 含有脂肪族衍生鏈、PEG衍生鏈、PEG衍生寡聚物或PEG衍生聚合物時，於熟習此技術之人士所習知的條件下，本發明之化合物可進一步經官能化、反應及調劑以生成本發明所請之額外化合物，該等額外化合物可用於且併入肝選擇性藥物投遞系統之調製劑(諸如可生物性降解之PLGA-b-PEG聚合物奈米粒子(參閱文獻Erica Locatelli et al.,J ournal of Nanoparticle Research,14,1316,(2012))和以脂質為底質之載台(諸如脂質體、脂質奈米粒子及安定核酸脂質奈米粒子(參閱文獻Sara Falsini et al.,Journal of Medicinal Chemistry,57,1138(2014)))。Particularly, when R 1 is an aliphatic chain derivative, PEG-derivatized chains, PEG-derivatized PEG-derivatized oligomer or polymer, persons skilled in this art at conventional conditions of the compound of the present invention can be further functionalized , reacting, and modulating to produce additional compounds of the present invention that can be used in and incorporated into modulators of a liver selective drug delivery system (such as biodegradable PLGA-b-PEG polymer nanoparticles) See the paper Erica Locatelli et al., J ournal of Nanoparticle Research, 14, 1316, (2012) and lipid-based substrates (such as liposomes, lipid nanoparticles, and nucleophilic lipid nanoparticles). Sara Falsini et al., Journal of Medicinal Chemistry, 57, 1138 (2014))).

藉由熟習此技術之人士所習知的方法，諸如層析及/或分級結晶、蒸餾及昇華，基於物理化學性質之差異，可 將非鏡像異構混合物分離成個別之非鏡像異構物。藉由令鏡像異構混合物與適當之光學活性化合物(例如手性輔助劑，諸如手性醇或Mosher氏醯基氯)反應、分離非鏡像異構物及轉化(例如水解)個別非鏡像異構物為對應之純鏡像異構物，經轉化鏡像異構混合物為非鏡像異構混合物可分離鏡像異構物。本發明之某些化合物亦可為構型異構物(例如經取代之聯芳)，其係屬本發明之一部分。藉由使用手性HPLC(高壓液相層析)管柱亦可分離鏡像異構物。Based on methods known to those skilled in the art, such as chromatography and/or fractional crystallization, distillation, and sublimation, based on differences in physicochemical properties, The non-imagewise isomeric mixture is separated into individual non-image isomers. By reacting a mirror image isomeric mixture with a suitable optically active compound (eg, a chiral auxiliary such as a chiral alcohol or Mosher's mercapto chloride), isolating the non-image isomers and converting (eg, hydrolyzing) individual non-image isomers The corresponding mirror image isomers are separated, and the mirror image isomers are separated by conversion of the mirror-isomeric mixture into a non-imagewise mixture. Certain compounds of the invention may also be configurational isomers (e.g., substituted biaryls) which are part of the present invention. The mirror image isomers can also be separated by using a chiral HPLC (high pressure liquid chromatography) column.

本發明之中間體和化合物亦可以不同之互變異構型式存在且本發明之範圍包含所有該等型式。“互變異構物”或“互變異構型式”係指不同能量之結構異構物，該等結構異構物經低能量障礙可互相轉化。例如，質子互變異構物(亦稱為質子轉移互變異構物)包括經由質子遷移之互相轉化型，諸如酮-烯醇和亞胺-烯胺異構化。質子互變異構物之一特定實例為咪唑團，其中質子可於2個環氮之間遷移。價互變異構物包括藉由重組某些鍵結電子之互相轉化型。某些中間體(及/或中間體之混合物)的閉型和開型之間的平衡係涉及醛糖之變旋過程，其係為熟習此技術之人士所習知。The intermediates and compounds of the invention may also exist in different tautomeric forms and the scope of the invention encompasses all such forms. "Tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible by low energy barriers. For example, proton tautomers (also known as proton transfer tautomers) include interconversions via proton transfer, such as keto-enol and imine-enamine isomerization. A specific example of a proton tautomer is an imidazole group in which protons can migrate between two ring nitrogens. Valence tautomers include interconversions by recombining certain bonded electrons. The balance between the closed form and the open form of certain intermediates (and/or mixtures of intermediates) involves the cyclization process of aldose, which is well known to those skilled in the art.

本發明亦包含本發明的經同位素標記之化合物，該等化合物與本發明所描述之化合物相同，唯其中一或多個原子係經具有與天然通常存在之原子量或質量數不同的原子量或質量數之原子替代。可併入本發明之化合物的同位素之實例包括氫、碳、氮、氧、磷、硫、氟、碘及氯之同位 素，分別諸如2 H、3 H、11 C、13 C、14 C、13 N、15 N、15 O、17 O、18 O、31 P、32 P、35 S、18 F、123 I、125 I及36 Cl。The invention also encompasses isotopically-labeled compounds of the invention which are identical to the compounds described herein, wherein one or more of the atomic systems have an atomic mass or mass number different from the atomic mass or mass number normally present in nature. The atom is replaced. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively. N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl.

本發明之某些經同位素標記之化合物(例如經3 H和14 C標記者)可用於化合物及/或受質組織分佈檢測。因易於製備和可偵測性，氚(即3 H)和碳-14(即14 C)同位素係特佳的。再者，經較重之同位素(諸如氘(即2 H))替代可提供因較佳之代謝安定性所產生的某些治療益處(例如增長之活體內半生期或減少之劑量需求)並因此可能於某些情況下係較佳的。正子發射同位素(諸如15 O、13 N、11 C及18 F)可用於正子發射斷層攝影術(PET)研究以檢驗受質佔據。通常藉由類似於該等反應圖及/或下述實施例所描述之方法，使用經同位素標記之反應劑以替代非經同位素標記之反應劑，可製備本發明之經同位素標記之化合物。Certain isotopically-labeled compounds of the invention (e.g., labeled with 3 H and 14 C) can be used for the detection of compound and/or texture tissue distribution. The ruthenium (ie, 3 H) and carbon-14 (ie, 14 C) isotopes are particularly preferred for ease of preparation and detectability. Furthermore, replacement with heavier isotopes such as deuterium (ie, 2 H) may provide certain therapeutic benefits resulting from better metabolic stability (eg, increased in vivo half-life or reduced dosage requirements) and thus may In some cases it is preferred. The positron-emitting isotopes (such as 15 O, 13 N, 11 C, and 18 F) can be used in positron emission tomography (PET) studies to examine the host occupancy. The isotope-labeled compounds of the present invention can generally be prepared by methods analogous to the reaction schemes and/or the methods described in the following examples, using isotopically labeled reactants in place of non-isotopically labeled reactants.

本發明之化合物可用於治療疾病、症狀及/或失調；因此，本發明之另一實施態樣係醫藥組成物，其包含治療有效量的本發明之化合物和醫藥上可接受之賦形劑、稀釋劑或載劑。本發明之化合物(亦包括本發明所使用之組成物和方法)亦可用於製造供本文所描述之治療性應用的藥物。The compounds of the invention are useful in the treatment of diseases, conditions and/or disorders; therefore, another embodiment of the invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable excipient, Diluent or carrier. The compounds of the invention (also including the compositions and methods used in the invention) can also be used in the manufacture of a medicament for use in the therapeutic applications described herein.

本發明之組成物可呈液體溶液(例如可注射之溶液和可輸入之溶液)。較佳型式取決於預定之施予模式和治療應用。典型之組成物係呈可注射之溶液或可輸入之溶液的型式，諸如類似於用於人體被動免疫者之組成物。一種施予模式係非經腸(例如靜脈內、皮下、腹膜內、肌內、皮 內及胸骨內)或藉由輸液技術之無菌可注射之液體或油質懸浮液的型式。熟習此技術之人士當能瞭解，取決於所欲之結果，施予途徑及/或模式將會改變。於一較佳實施態樣中，該抗體係經靜脈內輸入或注射施予。於另一較佳實施態樣中，該抗體係經肌內或皮下注射施予。The compositions of the present invention can be in the form of a liquid solution (e.g., an injectable solution and an input solution). The preferred version depends on the intended mode of administration and therapeutic application. Typical compositions are in the form of injectable solutions or solutions that can be administered, such as compositions similar to those used for passive immunization of humans. A mode of administration is parenteral (eg intravenous, subcutaneous, intraperitoneal, intramuscular, cutaneous) Types of sterile injectable liquid or oleaginous suspensions, either internally or in the sternum) or by infusion techniques. Those skilled in the art will understand that depending on the desired outcome, the route and/or mode of administration will change. In a preferred embodiment, the anti-system is administered by intravenous injection or injection. In another preferred embodiment, the anti-system is administered by intramuscular or subcutaneous injection.

治療性組成物典型上係無菌的且於製造和儲存條件下呈安定。Therapeutic compositions are typically sterile and stable under the conditions of manufacture and storage.

該組成物可被調製成溶液、微乳液、分散液或脂質體。藉由將所需用量的本發明之化合物併入適當之稀釋劑和如需要之上述成分之一或多成分之組合並隨後進行無菌處理(例如過濾除菌)可製備無菌可注射之溶液。通常，藉由將活性成分併入含有基礎分散基質和選自上述成分之所需其他成分的無菌載劑以製備分散液。依據習知技術，使用適當分散用之濕潤劑及懸浮劑或其他可接受之劑，可調製懸浮液。該無菌可注射之製劑亦可為於無毒性之非經腸可接受之稀釋劑或溶劑中的無菌可注射之溶液或懸浮液，例如1,3-丁二醇溶液。於可接受之載劑和溶劑中，可使用的是水、林格(Ringer)氏溶液及等滲性氯化鈉溶液。此外，可便利地使用無菌固定油作為溶劑或懸浮基質。對此目的，可使用任何溫和固定油，其包括合成單或二甘油酯。此外，正-3多不飽和脂肪酸可用於製備可注射劑。The composition can be formulated as a solution, microemulsion, dispersion or liposome. Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount, in a suitable diluent, and in a combination of one or more of the above ingredients as needed, followed by a sterile treatment (e.g., filter sterilization). In general, dispersions are prepared by incorporating the active ingredient into a dispersion vehicle containing the base dispersion base and the other ingredients selected from the above ingredients. The suspension may be prepared according to conventional techniques using humectants and suspending agents or other acceptable agents suitable for dispersion. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Further, a sterile fixed oil can be conveniently used as a solvent or a suspension matrix. For this purpose any bland fixed oil may be employed which includes synthetic mono or diglycerides. In addition, n-only polyunsaturated fatty acids can be used in the preparation of injectables.

於無菌粉末用於製備無菌可注射之溶液的情況下，較佳之製備方法係真空乾燥和冷凍乾燥以自先前經無菌過濾之溶液生成活性成分和任何額外所欲之成分的粉末。例 如，藉由使用塗覆(諸如卵磷脂)或於分散液之情況下藉由維持所需要之粒子大小及藉由使用界面活性劑，可維持溶液之適當流動性。Where a sterile powder is used in the preparation of a sterile injectable solution, the preferred method of preparation is vacuum drying and lyophilizing to produce a powder of the active ingredient and any additional desired ingredients from a previously sterilely filtered solution. example The proper fluidity of the solution can be maintained, for example, by the use of a coating such as lecithin or by the maintenance of the required particle size and by the use of a surfactant.

藉由於可注射之組成物中包括延長吸收劑(例如單硬脂酸鹽和明膠)或藉由將該可注射之組成物調製成延長吸收劑型(諸如儲積體、脂質體、聚合物微球、聚合物凝膠及移植體)，可導致該可注射之組成物的延長吸收。By including an extended absorbent (eg, monostearate and gelatin) or by injecting the injectable composition into a prolonged absorbent form (such as a reservoir, liposome, polymeric microsphere, Polymer gels and grafts) can result in prolonged absorption of the injectable compositions.

施予本發明之化合物的其他方法包括直接釋出藥物至個體皮膚之皮膚貼片。該等貼片可含有於可選擇地經緩衝之液體溶液中、溶解及/或分散於黏著劑中或分散於聚合物中的本發明之化合物。Other methods of administering the compounds of the invention include direct release of the drug to the skin patch of the individual's skin. The patches may be included in a selectively buffered liquid solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer.

該化合物可被施予一次，但亦可被施予多次。例如，該化合物可被施予自每天一次至每6個月或更久一次。該施予可經排程，諸如一天3次、一天2次、一天1次、每2天1次、每3天1次、每週1次、每2週1次、每個月1次、每2個月1次、每3個月1次及每6個月1次。The compound can be administered once, but can also be administered multiple times. For example, the compound can be administered from once a day to every 6 months or more. The administration can be scheduled, such as 3 times a day, 2 times a day, once a day, once every 2 days, once every 3 days, once a week, once every 2 weeks, once a month, every time. Once every 2 months, once every 3 months and once every 6 months.

該化合物亦可經微小泵連續施予。該化合物可被施予至染疾之身體部位處或該染疾之身體部位處的遠端。該化合物可被施予1次、至少2次或持續至少一段期間直至該疾病被治療、緩和或治癒。通常只要該疾病存在，該化合物可被一直施予。該化合物典型上可以所述之醫藥組成物的一部分被施予。The compound can also be administered continuously via a micro pump. The compound can be administered to the distal end of the body part where the disease is infected or at the body part of the affected disease. The compound can be administered once, at least 2 times or for at least a period of time until the disease is treated, alleviated or cured. The compound is usually administered as long as the disease is present. The compound is typically administered as part of the pharmaceutical composition described.

本發明之組成物可包括治療有效量或預防治療有效量的本發明之化合物。於製備本發明之組成物時，藉由例如 考量所欲之劑量體積和投藥模式、待被治療之病症的本性和嚴重性及個體之年齡和體重，可決定該組成物中該化合物之治療有效量。The compositions of the invention may comprise a therapeutically effective amount or a prophylactically effective amount of a compound of the invention. For preparing the composition of the present invention, for example by The therapeutically effective amount of the compound in the composition can be determined by considering the desired dosage volume and mode of administration, the nature and severity of the condition to be treated, and the age and weight of the individual.

施予個體的本發明之醫藥組成物的例示性且非限制性劑量範圍係自約0.01mg/kg至約200mg/kg(以毫克(mg)被施予之式(A)化合物/千克(kg)個體體重表示)、自約0.1mg/kg至約100mg/kg、自約1.0mg/kg至約50mg/kg、自約5.0mg/kg至約20mg/kg、或約15mg/kg。對本發明之目的，平均人體重量約70kg。本文所述之任何範圍的中間範圍，例如約0.02mg/kg至199mg/kg亦屬本發明之一部分。例如，本發明包括所述之任何值作為上限值及/或下限值的組合。Exemplary and non-limiting dosage ranges for the pharmaceutical compositions of the present invention administered to an individual range from about 0.01 mg/kg to about 200 mg/kg (in the form of milligrams (mg) of the compound of formula (A) per kilogram (kg). The individual body weight is expressed, from about 0.1 mg/kg to about 100 mg/kg, from about 1.0 mg/kg to about 50 mg/kg, from about 5.0 mg/kg to about 20 mg/kg, or about 15 mg/kg. For the purposes of the present invention, the average human body weight is about 70 kg. An intermediate range of any of the ranges described herein, for example from about 0.02 mg/kg to 199 mg/kg, is also part of the invention. For example, the invention includes any value recited as a combination of the upper and/or lower limit.

亦可調整劑量攝取方式以藉由經時施予個體數個分開之劑量而提供最佳之所欲反應(例如治療性或預防治療性反應)或於治療狀態之緊急事件下該劑量可經比例地降低或增加。因易於施予和劑量一致性，特別有利的是調製單位劑量型之非經腸組成物。The dosage regimen can also be adjusted to provide the optimal desired response (e.g., therapeutic or prophylactic therapeutic response) by administering a plurality of separate doses over time to the individual or in the event of an emergency in the therapeutic state. Decrease or increase. It is especially advantageous to modulate the unit dosage form of the parenteral composition for ease of administration and uniformity of dosage.

本發明所使用之單位劑量型係指適用於作為被治療之哺乳動物的單位劑量之物理上分開的單位；每個單位含有經計算能產生所欲的治療功效之預定量的活性化合物和需要的醫藥載劑。本發明之單位劑量型的規格係受制於且直接取決於(a)化合物或部分之獨一特性和欲達成之特定治療性或預防治療性功效、及(b)本質上存在於此技術中複合諸如抗體以治療個體之敏感度的限制。The unit dosage form as used in the present invention refers to physically discrete units suitable as unit dosages for the mammal being treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect and required Pharmaceutical carrier. The unit dosage form of the present invention is subject to and depends directly on (a) the unique properties of the compound or moiety and the particular therapeutic or prophylactic therapeutic effect desired, and (b) is essentially present in this technology. Limitations such as antibodies to treat the sensitivity of an individual.

本發明之液體組成物可經製備呈單位劑量型。例如，單位劑量/小瓶可含有1至1000毫升(ml)之不同濃度的式(A)化合物。於其他實施態樣中，單位劑量/小瓶可含有約1ml、2ml、3ml、4ml、5ml、6ml、7ml、8ml、9ml、10ml、15ml、20ml、30ml、40ml、50ml或100ml之不同濃度的式(A)化合物。若有需要，藉由加入無菌稀釋劑至每個小瓶，可調整該等製劑至所欲之濃度。本發明之液體組成物亦可經製備呈無菌袋或無菌容器之單位劑量型，該等單位劑量型適於與靜脈內投藥管或導管連結。The liquid compositions of the present invention can be prepared in unit dosage form. For example, the unit dose/vial can contain from 1 to 1000 milliliters (ml) of different concentrations of the compound of formula (A). In other embodiments, the unit dose/vial may contain different concentrations of about 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, 20 ml, 30 ml, 40 ml, 50 ml or 100 ml. (A) a compound. If desired, the formulations can be adjusted to the desired concentration by the addition of sterile diluent to each vial. The liquid compositions of the present invention may also be prepared in unit dosage forms in sterile or sterile containers suitable for attachment to an intravenous administration tube or catheter.

另一典型之調製劑係藉由本發明之化合物與載劑、稀釋劑或賦形劑混合而製得。適當之載劑、稀釋劑及賦形劑為熟習此技術之人士所習知且包括諸如碳水化合物、蠟、水溶性及/或可泡脹性聚合物、親水性或疏水性材料、明膠、油、溶劑、水及類似者之材料。所使用的特定載劑、稀釋劑或賦形劑將取決於施予本發明之化合物的方式及目的。溶劑通常係根據熟習此技術之人士認可為安全投予至哺乳動物的溶劑(GRAS)予以選擇。通常，安全溶劑為無毒水性溶劑(諸如水)及其他可溶於水或與水可混溶之無毒溶劑。適當水性溶劑包括水、乙醇、丙二醇、聚乙二醇(例如PEG400和PEG300)等及彼等之混合物。調製劑亦可包括一或多種緩衝劑、安定劑、界面活性劑、濕潤劑、潤滑劑、乳化劑、懸浮劑、防腐劑、抗氧化劑、不透明劑、助滑劑、加工助劑、著色劑、甜味劑、香料、調味劑及其他提供藥物(亦即本發明化合物或彼之醫藥組成物)之精美 外觀或有助於製造醫藥品(即藥物)的已知添加劑。Another typical modulating agent is prepared by mixing a compound of the present invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils , solvents, water and similar materials. The particular carrier, diluent or excipient used will depend on the mode and purpose of the compound of the invention. Solvents are generally selected according to a solvent (GRAS) approved by those skilled in the art for safe administration to mammals. Generally, the safe solvent is a non-toxic aqueous solvent such as water and other non-toxic solvents which are soluble in water or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400 and PEG 300), and the like, and mixtures thereof. The preparation agent may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, slip agents, processing aids, colorants, Sweeteners, flavors, flavorings and other exquisite medications (ie, the compounds of the invention or their pharmaceutical compositions) Appearance or a known additive that contributes to the manufacture of pharmaceuticals (ie drugs).

調製劑可使用慣用之溶解和混合步驟製備。例如，在一或多種上述賦形劑之存在下，將大量藥物(即本發明之化合物或該化合物之安定形式(例如與環糊精衍生物或其他已知錯合劑形成之錯合物))溶於適當之溶劑中。通常將本發明之化合物調製成醫藥劑型以提供易於控制的藥物劑量並為病患提供精美且易於處理之產物。Modulators can be prepared using conventional dissolution and mixing steps. For example, a large amount of a drug (i.e., a compound of the invention or a stable form of the compound (e.g., a complex formed with a cyclodextrin derivative or other known complexing agent) in the presence of one or more of the above-mentioned excipients) Soluble in a suitable solvent. The compounds of the present invention are typically formulated into pharmaceutical dosage forms to provide an easily controlled dosage of the drug and to provide the patient with a delicate and easy to handle product.

醫藥組成物亦包括式(I)化合物的溶劑化物及水合物。“溶劑化物”係指式(I)化合物(包括彼之醫藥上可接受之鹽)與一或多個溶劑分子之分子複合物。該等溶劑分子為常用於醫藥技術者且已知對接受者無害，例如水、乙醇、乙二醇及類似者。“水合物”係指其中溶劑分子為水的複合物。溶劑化物及/或水合物較佳地係以結晶形式存在。其他溶劑可用於製備較為所欲之溶劑化物的中間溶劑化物，該等溶劑係諸如甲醇、甲基第三丁醚、乙酸乙酯、乙酸甲酯、(S)-丙二醇、(R)-丙二醇、1,4-丁炔二醇及類似者。該結晶形式亦可以與其他無毒小分子(諸如L-***酸、L-脯胺酸、L-焦麩胺酸及類似者)之複合物、共結晶物或該共結晶物之溶劑化物或水合物存在。可使用PCT公開案號WO 08/002824所描述之方法或熟習此技術之人士所習知之其他方法以製備該等溶劑化物、水合物及共結晶化合物，該PCT公開案併入本發明作為參考。Pharmaceutical compositions also include solvates and hydrates of the compounds of formula (I). "Solvate" refers to a molecular complex of a compound of formula (I), including a pharmaceutically acceptable salt thereof, with one or more solvent molecules. Such solvent molecules are commonly used in medical technology and are known to be harmless to the recipient, such as water, ethanol, ethylene glycol and the like. "Hydrate" refers to a complex in which the solvent molecule is water. The solvates and/or hydrates are preferably present in crystalline form. Other solvents can be used to prepare intermediate solvates of the desired solvates such as methanol, methyl tert-butyl ether, ethyl acetate, methyl acetate, (S)-propylene glycol, (R)-propylene glycol, 1,4-butynediol and the like. The crystalline form may also be complexed with other non-toxic small molecules (such as L-phenylalanine, L-proline, L-pyramide, and the like), co-crystals or solvates or hydrates of the co-crystals. The object exists. Such solvates, hydrates, and co-crystal compounds can be prepared using the methods described in PCT Publication No. WO 08/002824, or other methods known to those skilled in the art, which is incorporated herein by reference.

用於施予之醫藥組成物(或調製劑)可視投予藥物所使用的方法而以各種方式包裝。通常，用於分配之物件包括 醫藥調製劑以適當形式存放於其中的容器。適當容器為熟習此技術之人士所習知者且包括諸如瓶子(塑膠和玻璃)、藥囊、安瓿、塑膠袋、金屬筒及類似者之材料。容器亦可包括防搗毀組件以防止輕率地接近包裝內容物。另外，說明容器內容物的標籤置於容器上。標籤亦可包括適當警語。The pharmaceutical composition (or modulator) for administration can be packaged in various ways depending on the method used to administer the drug. Typically, the items used for distribution include A container in which the pharmaceutical modulator is stored in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cans and the like. The container may also include an anti-smash component to prevent intimate access to the contents of the package. In addition, a label indicating the contents of the container is placed on the container. The tag can also include appropriate warnings.

藉由下述之實施方式說明本發明之實施態樣。然而，應當瞭解的是，本發明之實施態樣不受限於該實施方式之特定細節，因為彼等之其他變化將為熟習此技術之人士所習知或參閱本發明之揭露為明顯。Embodiments of the present invention will be described by way of the following embodiments. However, it should be understood that the invention is not limited by the specific details of the embodiments of the invention.

圖1表示實施例23化合物之精製晶體結構，該精製晶體結構係經使用SHELXTL繪圖套裝軟體以50%信賴水準繪製之橢球體繪製。Figure 1 shows the refined crystal structure of the compound of Example 23, which was drawn using an ellipsoid drawn with a SHELXTL drawing set software at 50% confidence level.

除非另有特別指明，起始物通常可得自商業來源，諸如Aldrich Chemicals Co.(Milwaukee,WI)、Lancaster Synthesis,Inc.(Windham,NH)、Acros Organics(Fairlawn,NJ)、Maybridge Chemical Company,Ltd.(Cornwall,England)、Tyger Scientific(Princeton,NJ)、AstraZeneca Pharmaceuticals(London,England)及Accela ChemBio(San Diego,CA)。Starting materials are generally available from commercial sources, such as Aldrich Chemicals Co. (Milwaukee, WI), Lancaster Synthesis, Inc. (Windham, NH), Acros Organics (Fairlawn, NJ), Maybridge Chemical Company, unless otherwise specifically indicated. Ltd. (Cornwall, England), Tyger Scientific (Princeton, NJ), AstraZeneca Pharmaceuticals (London, England) and Accela ChemBio (San Diego, CA).

一般實驗方法General experimental method

於室溫和400MHz(針對質子)下使用Varian UnityTM 400(購自Varian Inc.,Palo Alto,CA)記錄NMR光譜。化學位移係以相對於作為內部參考之殘餘溶劑的每百萬之份數(ppm；δ)表示。峰形表示如下：單峰(s)；雙峰(d)；雙峰之雙峰(dd)；三峰(t)；四峰(q)；多峰(m)；寬單峰(bs或br.s)；2個單峰(2s)；寬雙峰(br.d)。於某些情況下，僅提供代表性1 H NMR峰。使用BakerTM 矽膠(40微米；J.T.Baker,Phillipsburg,NJ)或矽膠50(EM SciencesTM ,Gibbstown,NJ)之管柱或Flash 40 BiotageTM 管柱(ISC,Inc.,Shelton,CT)實施管柱層析。使用BiotageTM SP純化系統或源自TeledyneTM IscoTM 之Combiflash® Companion® 實施中度壓力液相層析(MPLC)；於低氮氣壓下使用BiotageTM SNAP筒KPsil或Redisep Rf二氧化矽(購自TeledyneTM IscoTM )。除非另有註明，於氮氣惰性氛圍下使用無水溶劑進行所有反應。除非另有註明，亦於室溫(約23℃)下進行所有反應。當進行薄層層析(TLC)時，Rf 定義為化合物行進之距離/溶析液行進之距離的比值。Rt (滯留時間)。H-Cube®連續流氫化反應器：桌上型獨立氫化反應器，其組合連續流微化學與內生型需求性氫氣生成和可拋棄性觸媒筒系統。At room temperature using a Varian 400 MHz (for proton) under Unity TM 400 (available from Varian Inc., Palo Alto, CA) NMR spectra were recorded. The chemical shift is expressed in parts per million (ppm; δ) relative to the residual solvent as an internal reference. The peak shape is expressed as follows: single peak (s); double peak (d); doublet double peak (dd); three peaks (t); four peaks (q); multiple peaks (m); broad single peaks (bs or br .s); 2 single peaks (2s); wide double peaks (br.d). In some cases, only representative 1 H NMR peaks are provided. Baker TM silica gel using (40 microns; JTBaker, Phillipsburg, NJ), or silica gel 50 (EM Sciences TM, Gibbstown, NJ) column, or the Flash 40 Biotage TM column (ISC, Inc., Shelton, CT ) layer embodiments string Analysis. Using Biotage TM SP purification system or a Combiflash ® Companion ® from embodiment moderate pressure liquid chromatography (MPLC) Teledyne TM Isco TM of; low nitrogen pressure using Biotage TM SNAP cartridge or Redisep Rf KPsil silicon dioxide (available from Teledyne TM Isco TM). All reactions were carried out using an anhydrous solvent under a nitrogen inert atmosphere unless otherwise noted. All reactions were carried out at room temperature (about 23 ° C) unless otherwise stated. When performing thin layer chromatography (TLC), Rf is defined as the ratio of the distance traveled by the compound/the distance traveled by the eluent. R t (residence time). H-Cube® Continuous Flow Hydrogenation Reactor: A desktop independent hydrogenation reactor that combines continuous flow microchemistry with an endogenous demand hydrogen generation and disposable catalyst cartridge system.

LC/MS TOF(ESI)：所有數據係由Agilent 1100 LC(配備MSD TOF(Agilent模式G1969A)質譜儀偵測器且使用電 噴霧噴霧離子化源進行分析)產生。LC儀器包括二元泵(Agilent模式G1312A；低壓限制400巴)，其與自動取樣儀(Agilent模式G1313A)連接，該自動取樣儀使用外部工具以提交樣品。管柱間隔(Agilent模式G1316A)係與二極體陣列(Agilent模式G1315A)連接。使用Agilent MassHunter TOF/Q-TOF B.02(B11285)片1.2.3進行儀器取得和資料處理。洗提條件：管柱：未使用管柱；流體注射：注射體積1.0微升；流速：0.5ml/分鐘；進行時間：1.0分鐘；溶劑：甲醇(0.1%甲酸和0.05%甲酸銨)。TOF條件：離子化源：正向模式之電噴霧噴霧離子化源；氣體溫度：325℃；乾燥氣體；6升/分鐘；噴霧器：50psg；VCap：3500V；質量範圍110至100m/z；採集率：0.99光譜/秒；採集時間：1012.8毫秒/光譜。所有溶劑係屬HPLC層析溶解級(購自Sigma Aldrich(St.Louis,Missouri))。大部分化學品和緩衝劑係購自Sigma Aldrich且皆為純度97%或更高。LC/MS TOF (ESI): All data were from an Agilent 1100 LC equipped with an MSD TOF (Agilent Mode G1969A) mass spectrometer detector and used Spray spray ionization source for analysis). The LC instrument included a binary pump (Agilent mode G1312A; low pressure limit 400 bar) coupled to an autosampler (Agilent mode G1313A) that used an external tool to submit samples. The column spacing (Agilent mode G1316A) is connected to a diode array (Agilent mode G1315A). Instrument acquisition and data processing were performed using Agilent MassHunter TOF/Q-TOF B.02 (B11285) sheet 1.2.3. Stripping conditions: column: unused column; fluid injection: injection volume 1.0 microliter; flow rate: 0.5 ml/min; proceeding time: 1.0 minute; solvent: methanol (0.1% formic acid and 0.05% ammonium formate). TOF conditions: ionization source: electrospray spray ionization source in forward mode; gas temperature: 325 ° C; dry gas; 6 l / min; spray: 50 psg; VCap: 3500 V; mass range 110 to 100 m / z; : 0.99 spectrum / sec; acquisition time: 1012.8 ms / spectrum. All solvents were HPLC chromatographic grades (purchased from Sigma Aldrich (St. Louis, Missouri)). Most of the chemicals and buffers were purchased from Sigma Aldrich and were all 97% pure or higher.

方法C 1.5分鐘實施LRMS(低解析質譜)：水Acqity HSS T3,2.1mm×50mm,C18,1.7μm；移動相A：0.1%甲酸之水溶液(v/v)；移動相B：0.1%甲酸之乙腈溶液(v/v)；流速：1.25ml/分鐘；初始條件：A 95%：B 5%；初始維持0.0至0.1分鐘；線性上升至A 5%：B 95%達0.1至1.0分鐘；維持於A 5%：B 95%1.0至1.1分鐘；返回初始條件1.1至1.5分鐘。Method C LRMS (Low Analytical Mass Spectrometry) was performed for 1.5 minutes: water Acqity HSS T3, 2.1 mm x 50 mm, C18, 1.7 μm; mobile phase A: 0.1% formic acid in aqueous solution (v/v); mobile phase B: 0.1% formic acid Acetonitrile solution (v/v); flow rate: 1.25 ml/min; initial conditions: A 95%: B 5%; initial maintenance 0.0 to 0.1 minutes; linear rise to A 5%: B 95% for 0.1 to 1.0 minutes; At A 5%: B 95% 1.0 to 1.1 minutes; return to initial conditions 1.1 to 1.5 minutes.

方法C 3.0分鐘實施LRMS(低解析質譜)：水Acqity HSS T3,2.1mm×50mm,C18,1.7μm；移動相A：0.1%甲酸之水溶液(v/v)；移動相B：0.1%甲酸之乙腈溶液(v/v)；流速：1.25ml/分鐘；初始條件：A 95%：B 5%；初始維持0.0至0.1分鐘；線性上升至A 5%：B 95%達0.1至2.6分鐘；維持於A 5%：B 95% 2.6至2.95分鐘；返回初始條件2.95至3.0分鐘。Method C Perform LRMS (Low Analytical Mass Spectrometry) in 3.0 min: Water Acqity HSS T3, 2.1 mm x 50 mm, C18, 1.7 μm; mobile phase A: 0.1% formic acid in water (v/v); mobile phase B: 0.1% formic acid in acetonitrile (v/v); flow rate: 1.25 ml/min Initial conditions: A 95%: B 5%; initial maintenance 0.0 to 0.1 minutes; linear rise to A 5%: B 95% for 0.1 to 2.6 minutes; maintained at A 5%: B 95% 2.6 to 2.95 minutes; The initial conditions are 2.95 to 3.0 minutes.

步驟step ((2R,3S,4R,5R,6R)-5-疊氮基-6-甲氧基-3,4-雙((三甲基矽基)氧基)四氫-2H-哌喃-2-基)甲醇(I-b)((2R,3S,4R,5R,6R)-5-azido-6-methoxy-3,4-bis((trimethylmethyl)oxy)tetrahydro-2H-pyran-2 -base)methanol (Ib)

令(2R,3R,4R,5R,6R)-5-疊氮基-2-(羥基甲基)-6-甲氧基四氫-2H-哌喃-3,4-二醇(I-a)(5g,23毫莫耳)溶解於無水吡啶(100ml)中並加入三甲基矽基氯(17.5ml,139毫莫耳)。令反應混合物於室溫下經攪拌12小時並隨後蒸發吡啶。將殘餘物置入乙酸乙酯/水中。令水相經乙酸乙酯萃取1次並令結合之有機層經水和飽和氯化鈉水溶液沖洗，置於硫酸鎂上乾燥且經過濾和濃縮以生成呈黃色油之對應的全甲矽烷基化化合物(9.9g,98%產率)。該產物未經任何進一步純化而用於下一個步驟。對經冷卻至0℃之上述全甲矽烷基化化合物(9.71g,22.3毫莫耳)之無水甲醇(45ml)溶液加入碳酸鉀之甲醇溶液(0.032M,9.06ml)。令反應混合 物於0℃下經攪拌1小時並隨後經加入之乙酸(17ml)中和。蒸發溶劑並令殘餘物溶解於乙酸乙酯。加入水並令水相經乙酸乙酯萃取2次。令結合之有機層經鹽水沖洗，置於硫酸鎂上乾燥並經過濾和濃縮。令粗產物經矽膠閃爍層析(30%乙酸乙酯/己烷)純化以生成呈油之化合物(I-b)(6.77g,84%)。[α]D 7(c 1，氯仿)；1 H NMR(400MHz，氯仿-d)δ ppm 0.14(s,9H),0.20(s,9H),1.80(br.s.,1H),3.36-3.42(m,1H),3.45(dd,J=7.3,4.6Hz,1H),3.54(dd,J=10.0,8.0Hz,1H),3.59(s,3H),3.65(dd,J=11.3,4.7Hz,1H),3.77(d,J=2.7Hz,1H),3.87(dd,J=11.2,7.3Hz,1H),4.14(d,J=8.0Hz,1H)；13 C NMR(100MHz，氯仿-d)δ ppm 0.27(3C),0.6(3C),57.3,62.6,64.0,71.1,73.7,75.2,103.4；HRMS(ESI)經計算C13 H29 N3 O5 Si2 (m/z)[M+Na]+ 386.1538，結果386.1539。(2R,3R,4R,5R,6R)-5-azido-2-(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4-diol (Ia) ( 5 g, 23 mmoles were dissolved in anhydrous pyridine (100 ml) and trimethyldecyl chloride (17.5 ml, 139 mmol) was added. The reaction mixture was allowed to stir at room temperature for 12 hours and then pyridine was evaporated. The residue was taken up in ethyl acetate / water. The aqueous phase was extracted once with ethyl acetate and the combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and filtered and concentrated to give the corresponding y Compound (9.9 g, 98% yield). This product was used in the next step without any further purification. A solution of the above potassium methacrylate compound (9.71 g, 22.3 mmol) in anhydrous methanol (45 ml The reaction mixture was stirred at 0 ° C for 1 hour and then neutralized with acetic acid (17 mL). The solvent was evaporated and the residue was dissolved in ethyl acetate. Water was added and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered and concentrated. The crude product was purified by silica gel chromatography (30% ethyl acetate / hexane) to afford compound (Ib) (6.77 g, 84%). [α] D 7(c 1, chloroform); 1 H NMR (400 MHz, chloroform-d) δ ppm 0.14 (s, 9H), 0.20 (s, 9H), 1.80 (br.s., 1H), 3.36- 3.42 (m, 1H), 3.45 (dd, J = 7.3, 4.6 Hz, 1H), 3.54 (dd, J = 10.0, 8.0 Hz, 1H), 3.59 (s, 3H), 3.65 (dd, J = 11.3, 4.7 Hz, 1H), 3.77 (d, J = 2.7 Hz, 1H), 3.87 (dd, J = 11.2, 7.3 Hz, 1H), 4.14 (d, J = 8.0 Hz, 1H); 13 C NMR (100 MHz, Chloroform-d) δ ppm 0.27 (3C), 0.6 (3C), 57.3, 62.6, 64.0, 71.1, 73.7, 75.2, 103.4; HRMS (ESI) calculated C 13 H 29 N 3 O 5 Si 2 (m/z )[M+Na] + 386.1538, the result 386.1539.

(3R,4R,5R,6R)-5-疊氮基-2,2-雙(羥基甲基)-6-甲氧基四氫-2H-哌喃-3,4-二醇(I-c)(3R,4R,5R,6R)-5-azido-2,2-bis(hydroxymethyl)-6-methoxytetrahydro-2H-pyran-3,4-diol (I-c)

令化合物(I-b)(7.73g,21.3毫莫耳)溶解於二氯甲烷(70ml)。加入二甲亞碸(10.6ml,150毫莫耳)和三乙胺(9ml,60毫莫耳)並令反應混合物冷卻至0℃。加入三氧化硫吡啶錯合物(10.2g,64毫莫耳)並令混合物於0℃下經攪拌 1小時且隨後經30分鐘回溫至室溫。令反應物經飽和氯化鈉溶液驟冷並經二氯甲烷萃取。令水相經二氯甲烷萃取3次並令結合之有機層經飽和氯化鈉水溶液沖洗，置於硫酸鎂上乾燥且經過濾和濃縮以生成對應之醛。令該醛溶解於無水乙醇(106ml)並先後加入聚甲醛粉末(40.3g,425毫莫耳)和21重量%乙氧化鈉之乙醇溶液(16ml,42.5毫莫耳)。令反應混合物於室溫下經攪拌12小時並隨後蒸發乙醇。對粗混合物加入甲醇並令固體經過濾且經甲醇完全輕洗。對含有所欲產物之濾液加入矽膠並蒸發甲醇。令所生成之乾產物於高真空下經乾燥並載入管柱。令粗產物經矽膠閃爍層析(10%甲醇/二氯甲烷)純化以生成呈無色油之化合物(I-c)(3.03g,57%；經2步驟)。[α]D -20(c 1.25，甲醇)；1 H NMR(400MHz，甲醇-d4 )δ ppm 3.46(dd,J=10.2,8.1Hz,1H),3.51(s,3H),3.64-3.80(m,5H),3.80-3.83(m,1H),4.54(d,J=8.0Hz,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 57.2,61.2,63.6,65.9,69.9,71.2,80.9,101.2；HRMS(ESI)經計算C8 H15 N3 O6 (m/z)[M+Na]+ 272.0853，結果272.0856。Compound (Ib) (7.73 g, 21.3 mmol) was dissolved in dichloromethane (70 ml). Dimethyl hydrazine (10.6 ml, 150 mmol) and triethylamine (9 ml, 60 mmol) were added and the reaction mixture was cooled to 0 °C. Sulfur trioxide pyridine complex (10.2 g, 64 mmol) was added and the mixture was stirred at 0 °C for 1 hour and then warmed to room temperature over 30 minutes. The reaction was quenched with saturated aqueous sodium chloride and extracted with dichloromethane. The aqueous phase was extracted three times with dichloromethane and the combined organic layers were washed with saturated aqueous sodium chloride, dried over magnesium sulfate and filtered and concentrated to give the corresponding aldehyde. The aldehyde was dissolved in absolute ethanol (106 ml) and a solution of polyformaldehyde powder (40.3 g, 425 mmol) and 21% by weight of sodium ethoxide in ethanol (16 ml, 42.5 mmol). The reaction mixture was allowed to stir at room temperature for 12 hours and then ethanol was evaporated. Methanol was added to the crude mixture and the solid was filtered and washed thoroughly with methanol. The gum containing the desired product is added to the gum and the methanol is evaporated. The resulting dry product is dried under high vacuum and loaded onto the column. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) [α] D -20 (c 1.25, methanol); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 3.46 (dd, J = 10.2, 8.1 Hz, 1H), 3.51 (s, 3H), 3.64-3.80 (m, 5H), 3.80-3.83 (m, 1H), 4.54 (d, J = 8.0 Hz, 1H); 13 C NMR (100 MHz, methanol - d 4 ) δ ppm 57.2, 61.2, 63.6, 65.9, 69.9, 71.2,80.9,101.2; HRMS (ESI) calculated C 8 H 15 N 3 O 6 (m / z) [m + Na] + 272.0853, 272.0856 results.

N-((3aR,4S,7S,8R,8aR)-4-(羥基甲基)-2,2-二甲基六氫-4,7-環氧[1,3]二噁呃並[4,5-d]噁呯-8-基)乙醯胺(I-e-1)N-((3aR,4S,7S,8R,8aR)-4-(hydroxymethyl)-2,2-dimethylhexahydro-4,7-epoxy[1,3]dioxime[4 ,5-d]oxan-8-yl)acetamide (Ie-1)

對化合物(3)(230mg,0.986毫莫耳)之二甲基甲醯胺(6.6ml)溶液先後加入2,2-二甲氧基丙烷(0.8ml,6毫莫耳)和(+/-)-樟腦-10-磺酸(101mg,0.435毫莫耳)。令反應混合物於70℃下經攪拌24小時，冷卻至室溫並隨後加入甲醇(1.2ml)。令該反應混合物於室溫下經攪拌30分鐘並隨後經三乙胺(56微升)中和。蒸發溶劑並令殘餘物與甲苯共蒸發3次。令粗產物經矽膠閃爍層析(15/1乙酸乙酯/甲醇)純化以生成呈白色固體之化合物(I-e-1)(246mg,91%產率)。m.p.：164.7-166.0℃；[α]D 147(c 1，甲醇)；1 H NMR(400MHz，甲醇-d4 )δ ppm 1.34(s,3H),1.48(s,3H),1.98(s,3H),3.77(d,J=7.8Hz,1H),3.83(d,J=7.8Hz,1H),3.86(d,J=11.6Hz,1H),3.90(d,J=11.3Hz,1H),3.91-3.94(m,1H),4.14-4.19(m,1H),4.29(d,J=6.0Hz,1H),5.23(d,J=2.0Hz,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.7,26.9,28.5,56.8,61.9,70.2,76.1,76.6,83.0,102.6,112.5,173.6；HRMS(ESI)經計算C12 H19 NO6 (m/z)[M+H]+ 274.1285，結果274.1274。To a solution of compound (3) (230 mg, 0.986 mmol) in dimethylformamide (6.6 ml) was added 2,2-dimethoxypropane (0.8 ml, 6 mmol) and (+/-) ) - Camphor-10-sulfonic acid (101 mg, 0.435 mmol). The reaction mixture was stirred at 70 ° C for 24 hours, cooled to room temperature and then methanol (1.2 mL). The reaction mixture was allowed to stir at room temperature for 30 minutes and then neutralized with triethylamine (56 liters). The solvent was evaporated and the residue was co-evaporated three times with toluene. The crude product was purified by EtOAc EtOAc (EtOAc) elute Mp: 164.7-166.0 ° C; [α] D 147 (c 1, methanol); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.34 (s, 3H), 1.48 (s, 3H), 1.98 (s, 3H), 3.77 (d, J = 7.8 Hz, 1H), 3.83 (d, J = 7.8 Hz, 1H), 3.86 (d, J = 11.6 Hz, 1H), 3.90 (d, J = 11.3 Hz, 1H) , 3.91-3.94 (m, 1H), 4.14 - 4.19 (m, 1H), 4.29 (d, J = 6.0 Hz, 1H), 5.23 (d, J = 2.0 Hz, 1H); 13 C NMR (100 MHz, methanol -d 4 ) δ ppm 22.7, 26.9, 28.5, 56.8, 61.9, 70.2, 76.1, 76.6, 83.0, 102.6, 112.5, 173.6; HRMS (ESI) calculated C 12 H 19 NO 6 (m/z) [M+ H] + 274.1285, the result is 274.1274.

(1S,2R,3R,4R,5S)-4-疊氮基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二醇(1)(1S, 2R, 3R, 4R, 5S)-4-azido-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3-diol (1 )

令該四醇(I-c)(3g,12毫莫耳)溶解於水(40ml)並加入 濃硫酸(6.7ml)。令反應混合物於100℃下經攪拌40小時，冷卻至室溫並隨後經加入濃氫氧化銨中和。蒸發水並加入甲醇至所生成之混合物。令固體經過濾且經甲醇充分輕洗。對含有所欲產物之濾液加入矽膠並蒸發甲醇。令所生成之乾載物經高真空下乾燥並載入管柱。令粗產物經矽膠閃爍層析(10%甲醇/二氯甲烷)純化以生成呈無色油之化合物(1)(2.2g,84%產率)。[α]D 160(c 1.1，甲醇)；1 H NMR(400MHz，甲醇-d4 )δ ppm 3.35(dd,J=9.2,1.6Hz,1H),3.70(d,J=8.2Hz,1H),3.76(d,J=8.0Hz,1H),3.80(d,J=11.3Hz,1H),3.83-3.89(m,2H),3.90(d,J=11.5Hz,1H),5.32(d,J=1.4Hz,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 61.9,66.1,69.5,69.6,71.0,85.3,102.7；HRMS(ESI)經計算C7 H11 N3 O5 (m/z)[M+Na]+ 240.0591，結果240.0596。The tetraol (Ic) (3 g, 12 mmol) was dissolved in water (40 ml) and concentrated sulfuric acid (6.7 ml) was added. The reaction mixture was stirred at 100 ° C for 40 hours, cooled to room temperature and then neutralized by addition of concentrated ammonium hydroxide. The water was evaporated and methanol was added to the resulting mixture. The solid was filtered and washed thoroughly with methanol. The gum containing the desired product is added to the gum and the methanol is evaporated. The resulting dry charge is dried under high vacuum and loaded onto the column. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) [α] D 160 (c 1.1, methanol); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 3.35 (dd, J = 9.2, 1.6 Hz, 1H), 3.70 (d, J = 8.2 Hz, 1H) , 3.76 (d, J = 8.0 Hz, 1H), 3.80 (d, J = 11.3 Hz, 1H), 3.83 - 3.89 (m, 2H), 3.90 (d, J = 11.5 Hz, 1H), 5.32 (d, J = 1.4 Hz, 1H); 13 C NMR (100 MHz, methanol-d 4 ) δ ppm 61.9, 66.1, 69.5, 69.6, 71.0, 85.3, 102.7; HRMS (ESI) calculated C 7 H 11 N 3 O 5 ( m/z) [M+Na] + 240.0591.

二乙酸(1R,2R,3R,4R,5S)-4-乙醯胺基-1-(乙醯氧基甲基)-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二基酯(2)Diacetic acid (1R, 2R, 3R, 4R, 5S)-4-acetamido-1-(ethyloxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2, 3-diester (2)

於圓底燒瓶中，令化合物(1)(1.93g,8.9毫莫耳)溶解於乙醇(45ml)並令該系統經氮氣沖洗。加入林德拉(Lindlar)觸媒(1.89g,0.9毫莫耳)並令該系統先後經氮氣和氫氣沖洗。令反應混合物於室溫和氫氣氛圍(使用球)下 經攪拌24小時。使用耐隆(nylon)膜過濾鈀並先後經甲醇和水充分輕洗。蒸發溶劑並令殘餘物溶解於水且經冷凍乾燥。令所生成之粗產物隨後溶解於吡啶(40ml)並加入乙酸酐(9ml,100毫莫耳)。令反應混合物於室溫下經攪拌48小時並蒸發吡啶。令殘餘物溶解於乙酸乙酯並經飽和碳酸氫鈉溶液沖洗。令水相經乙酸乙酯萃取2次並隨後令結合之有機層經飽和氯化鈉水溶液沖洗，置於硫酸鎂上乾燥且經過濾和蒸發。令粗產物經矽膠閃爍層析(3%甲醇/二氯甲烷)純化以生成化合物(2)(3.19g，定量)。[α]D 75(c 1，氯仿)；1 H NMR(400MHz，甲醇-d4 )δ ppm 1.95(s,3H),1.95(s,3H),2.04(s,3H),2.15(s,3H),3.75(d,J=8.6Hz,1H),4.06(d,J=8.6Hz,1H),4.13(d,J=11.6Hz,1H),4.20(d,J=10.6Hz,1H),4.46(d,J=11.3Hz,1H),5.13(dd,J=10.4,4.4Hz,1H),5.35(d,J=1.0Hz,1H),5.38(d,J=4.3Hz,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 20.6,20.7(2C),22.6,53.3,63.0,68.9,69.1,70.3,82.6,103.0,171.8,171.9,172.1,173.8；HRMS(ESI)經計算C15 H21 NO9 (m/z)[M+H]+ 360.1289，結果360.1290。In a round bottom flask, Compound (1) (1.93 g, 8.9 mmol) was dissolved in ethanol (45 mL) and the system was flushed with nitrogen. Lindlar catalyst (1.89 g, 0.9 mmol) was added and the system was flushed with nitrogen and hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (using a ball) for 24 hours. The palladium was filtered using a nylon membrane and washed thoroughly with methanol and water. The solvent was evaporated and the residue was dissolved in water and lyophilized. The crude product formed was then dissolved in pyridine (40 mL) and acetic anhydride (9 mL, 100 m.m.). The reaction mixture was stirred at room temperature for 48 hours and pyridine was evaporated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The aqueous phase was extracted twice with ethyl acetate and then the combined organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and filtered and evaporated. The crude product was purified by silica gel flash chromatography (EtOAc/EtOAc) to afford Compound (2) (3.19 g, quantitative). [α] D 75 (c 1, chloroform); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.95 (s, 3H), 1.95 (s, 3H), 2.04 (s, 3H), 2.15 (s, 3H), 3.75 (d, J = 8.6 Hz, 1H), 4.06 (d, J = 8.6 Hz, 1H), 4.13 (d, J = 11.6 Hz, 1H), 4.20 (d, J = 10.6 Hz, 1H) , 4.46 (d, J = 11.3 Hz, 1H), 5.13 (dd, J = 10.4, 4.4 Hz, 1H), 5.35 (d, J = 1.0 Hz, 1H), 5.38 (d, J = 4.3 Hz, 1H) 13 C NMR (100 MHz, methanol-d 4 ) δ ppm 20.6, 20.7 (2C), 22.6, 53.3, 63.0, 68.9, 69.1, 70.3, 82.6, 103.0, 171.8, 171.9, 172.1, 173.8; HRMS (ESI) Calculated for C 15 H 21 NO 9 (m/z) [M+H] + 360.1289.

N-((1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)乙醯胺(3)N-((1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl)B Guanamine (3)

令化合物(2)(3.19g,8.88毫莫耳)溶解於四氫呋喃(50ml)並加入0.5M甲氧化鈉之甲醇溶液(100ml,50毫莫耳)。令反應混合物於室溫下經攪拌12小時並隨後經加入H+ AmberlyteTM IR-120樹脂中和。過濾樹脂並蒸發溶劑以生成呈白色固體之化合物(3)(1.71g,83%)。m.p.：175.7-176.1℃；[α]D 164(c 1，甲醇)；1 H NMR(400MHz，甲醇-d4 )δ ppm 1.99(s,3H),3.68(d,J=8.1Hz,1H),3.70-3.73(m,1H),3.75(d,J=7.8Hz,1H),3.81(d,J=11.3Hz,1H),3.87(d,J=4.3Hz,1H),3.92(d,J=11.3Hz,1H),3.95(dd,J=9.9,1.1Hz,1H),5.22(d,J=1.3Hz,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.7,56.4,62.1,69.2,69.3,70.6,85.1,102.8,174.1；HRMS(ESI)經計算C9 H15 NO6 (m/z)[M+H]+ 234.0972，結果234.0974。Compound (2) (3.19 g, 8.88 mmol) was dissolved in tetrahydrofuran (50 ml) and 0.5 M sodium hydroxide in methanol (100 ml, 50 m. The reaction mixture was allowed to stir at room temperature for 12 hours and then neutralized by addition of H + Amberlyte TM IR-120 resin. The resin was filtered and the solvent was evaporated to give compound (3) (1.71 g, 83%). Mp: 175.7-176.1 ° C; [α] D 164 (c 1, methanol); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.99 (s, 3H), 3.68 (d, J = 8.1 Hz, 1H) , 3.70-3.73 (m, 1H), 3.75 (d, J = 7.8 Hz, 1H), 3.81 (d, J = 11.3 Hz, 1H), 3.87 (d, J = 4.3 Hz, 1H), 3.92 (d, J = 11.3 Hz, 1H), 3.95 (dd, J = 9.9, 1.1 Hz, 1H), 5.22 (d, J = 1.3 Hz, 1H); 13 C NMR (100 MHz, methanol - d 4 ) δ ppm 22.7, 56.4 , 62.1,69.2,69.3,70.6,85.1,102.8,174.1; HRMS (ESI) calculated C 9 H 15 NO 6 (m / z) [m + H] + 234.0972, 234.0974 results.

(4-((2-((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)乙基)胺基)-4-側氧基丁基)胺甲酸芾酯(4)、(4-((1,3-雙((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)丙-2-基)胺基)-4-側氧基丁基)胺甲酸芾酯(5)及(4-((1,3-雙((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)-2-(((1-(1-((1S,2R,3R,4R,5S)- 4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)甲基)丙-2-基)胺基)-4-側氧基丁基)胺甲酸苄酯(6)(4-((2-(1-((1S,2R,3R,4R,5S)-4-Ethylamino-2,3-dihydroxy-6,8-dioxabicyclo[ 3.2.1] Oct-1-yl)-2,5,8,11-tetraoxatridecane-13-yl)-1H-1,2,3-triazol-4-yl)methoxy) Ethyl)amino)-4-oxobutylbutyl)carbazate (4), (4-((1,3-((1S,2R,3R,4R, 5S)-4-Ethylamino-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl)-2,5,8,11-tetraoxa 13 Alkyl-13-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-oxobutylbutyl)carbazate (5 And (4-((1,3-((1S,2R,3R,4R,5S)-4-ethylamino)-2,3-dihydroxy-6,8- Dioxabicyclo[3.2.1]oct-1-yl)-2,5,8,11-tetraoxatridecane-13-yl)-1H-1,2,3-triazol-4-yl )methoxy)-2-(((1-(1-((1S,2R,3R,4R,5S))) 4-Ethylamino-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl)-2,5,8,11-tetraoxatridecane-13 -yl)-1H-1,2,3-triazol-4-yl)methoxy)methyl)propan-2-yl)amino)-4-oxobutylbutyl) benzyl carbamate (6 )

於微波小管中，令化合物(I-e-1)(50mg,0.18毫莫耳)溶解於二氯甲烷(1ml)。加入12.5M氫氧化鈉水溶液(0.5ml)且隨後加入15-冠-5-醚(5μl,0.02毫莫耳)和1-疊氮基-2-(2-(2-(2-碘乙氧基)乙氧基)乙氧基)乙烷(描述於文獻J.Am.Chem.Soc.132,1523(2010)；301mg,0.915毫莫耳)。令反應混合物於55℃下經激烈攪拌24小時。移除有機相並置於硫酸鎂上乾燥且經過濾和濃縮。令粗產物經矽膠閃爍層析(5%甲醇/乙酸乙酯)純化以生成呈油之化合物(I-e-2)(52mg,60%產率)。[α]D 74(c 1，氯仿)；1 H NMR(400MHz，甲醇-d4 )δ ppm 1.34(s,3H),1.49(s,3H),1.98(s,3H),3.37(t,J=4.9Hz,2H),3.62-3.71(m,14H),3.75-3.80(m,2H),3.86(d,J=8.1Hz,1H)3.90-3.97(m,2H),4.12-4.19(m,1H),4.31(d,J=5.8Hz,1H),5.23(d,J=2.0 Hz,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.7,26.9,28.5,51.9,56.7,70.9,71.1,71.3,71.6,71.7,71.8,71.81,71.82,72.7,76.1,76.5,82.1,102.4,112.4,173.6；HRMS(ESI)經計算C20 H34 N4 O9 (m/z)[M+H]+ 475.2399，結果475.2386。Compound (Ie-1) (50 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml) in a microwave. Add 12.5 M aqueous sodium hydroxide solution (0.5 ml) and then add 15-crown-5-ether (5 μl, 0.02 mmol) and 1-azido-2-(2-(2-(2-iodoethoxy) Ethyl)ethoxy)ethane (described in J. Am. Chem. Soc. 132, 1523 (2010); 301 mg, 0.915 mmol). The reaction mixture was stirred vigorously at 55 ° C for 24 hours. The organic phase was removed and dried over magnesium sulfate and filtered and concentrated. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) [α] D 74 (c 1, chloroform); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.34 (s, 3H), 1.49 (s, 3H), 1.98 (s, 3H), 3.37 (t, J=4.9 Hz, 2H), 3.62-3.71 (m, 14H), 3.75-3.80 (m, 2H), 3.86 (d, J = 8.1 Hz, 1H) 3.90-3.97 (m, 2H), 4.12-4.19 ( m,1H), 4.31 (d, J = 5.8 Hz, 1H), 5.23 (d, J = 2.0 Hz, 1H); 13 C NMR (100 MHz, methanol - d 4 ) δ ppm 22.7, 26.9, 28.5, 51.9, 56.7, 70.9, 71.1, 71.3, 71.6, 71.7, 71.8, 71.81, 71.82, 72.7, 76.1, 76.5, 82.1, 102.4, 112.4, 173.6; HRMS (ESI) calculated C 20 H 34 N 4 O 9 (m/z )[M+H] + 475.2399, the result is 475.2386.

中間體(I-f-1)係習知且描述於WO 06/120545。The intermediate (I-f-1) is conventional and described in WO 06/120545.

可以下述方法合成中間體(I-f-2)：室溫下對Boc-絲胺醇(1000mg,5.1毫莫耳)之四氫呋喃(21ml)溶液加入碘化四丁基銨(287mg,0.76毫莫耳)、碘化鈉(153mg,1.02毫莫耳)及3-溴丙炔(1.8ml,16毫莫耳，80%甲苯溶液)。經30分鐘分批加入氫氧化鉀(569mg,10.1毫莫耳)並隨後令混合物於室溫下經攪拌16小時。令反應混合物經乙酸乙酯和水稀釋。令水相經乙酸乙酯萃取1次。令結合之有機層置於硫酸鎂上乾燥且經過濾和濃縮。令粗產物經矽膠閃爍層析(30%乙酸乙酯/己烷)純化以生成呈油之化合物(I-f-2)(530mg,39%產率)。1 H NMR(400MHz，氯仿-d/TMS)δ ppm 1.44(s,9H),2.44(t,J=2.4Hz,2H),3.53-3.67(m,4H),3.92(br.s.,1H),4.16(d,J=2.5Hz,4H),4.90(br.s.,1H)；13 C NMR(100MHz，氯仿-d/TMS)δ ppm 28.4(3C),49.5,58.5(2C),68.6(2C),74.6(2C),77.2,79.5(2C), 155.4；HRMS(ESI)經計算C14 H21 NO4 (m/z)[M+H]+ 268.1543，結果268.1536。The intermediate (If-2) can be synthesized by adding a solution of Boc-seramine (1000 mg, 5.1 mmol) in tetrahydrofuran (21 ml) at room temperature to tetrabutylammonium iodide (287 mg, 0.76 mmol). ), sodium iodide (153 mg, 1.02 mmol) and 3-bromopropyne (1.8 ml, 16 mmol, 80% in toluene). Potassium hydroxide (569 mg, 10.1 mmol) was added portionwise over 30 minutes and then the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and water. The aqueous phase was extracted once with ethyl acetate. The combined organic layers were dried over magnesium sulfate and filtered and concentrated. The crude product was purified by EtOAc (EtOAc) elute 1 H NMR (400MHz, CHLOROFORM -d / TMS) δ ppm 1.44 ( s, 9H), 2.44 (t, J = 2.4Hz, 2H), 3.53-3.67 (m, 4H), 3.92 (br.s., 1H ), 4.16 (d, J = 2.5 Hz, 4H), 4.90 (br.s., 1H); 13 C NMR (100 MHz, chloroform-d/TMS) δ ppm 28.4 (3C), 49.5, 58.5 (2C), 68.6 (2C), 74.6 (2C), 77.2, 79.5 (2C), 155.4; HRMS (ESI) Calculated C 14 H 21 NO 4 (m/z) [M+H] + 268.1543.

中間體(I-f-3)係習知且描述於文獻R.Roy et al.J.Org.Chem.73,5602(2008)。The intermediate (I-f-3) is conventionally described and described in the literature by R. Roy et al. J. Org. Chem. 73, 5602 (2008).

令化合物(I-f-1)、(I-f-2)或(I-f-3)(1當量)溶解於二氯甲烷(0.2M)並加入4M氯化氫之二噁烷溶液(5至10當量)。令反應混合物於室溫下經攪拌2至3小時並隨後蒸發溶劑。令殘餘物經高真空下乾燥1小時。所生成之中間體未經任何進一步純化而用於下一個步驟。令上述所生成之中間體(1當量)和4-(((苄氧基)羰基)胺基)丁酸(1當量)溶解於二噁烷與二甲基甲醯胺(0.09M；3：1)之混合物。先後加入六氟磷酸(苯並***-1-基氧基)三吡咯啶鏻(1.2當量)和N,N-二異丙基乙胺(5當量)。令反應混合物於室溫下經攪拌16小時。加入二氯甲烷和水並令水相經二氯甲烷萃取2次。令結合之有機層置於硫酸鎂上乾燥且經過濾和濃縮。令粗產物溶解於最少量之甲苯，經載入管柱且經矽膠閃爍層析純化。Compound (I-f-1), (I-f-2) or (I-f-3) (1 equivalent) was dissolved in dichloromethane (0.2 M) and 4M hydrogen chloride in dioxane (5 to 10 equivalents) was added. The reaction mixture was allowed to stir at room temperature for 2 to 3 hours and then the solvent was evaporated. The residue was dried under high vacuum for 1 hour. The resulting intermediate was used in the next step without any further purification. The intermediate (1 equivalent) and 4-(((benzyloxy))carbonyl)butyric acid (1 equivalent) obtained above were dissolved in dioxane and dimethylformamide (0.09M; 1) a mixture. Hexafluorophosphoric acid (benzotriazol-1-yloxy)tripyrrolidinium (1.2 equivalents) and N,N-diisopropylethylamine (5 equivalents) were added successively. The reaction mixture was allowed to stir at room temperature for 16 hours. Dichloromethane and water were added and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate and filtered and concentrated. The crude product was dissolved in a minimum of toluene, loaded onto a column and purified by silica gel flash chromatography.

中間體(I-g-1)：純化條件：100%乙酸乙酯，定量，油。1 H NMR(400MHz，氯仿-d/TMS)δ ppm 1.80-1.91(m,2H),2.24(t,J=7.1Hz,2H),2.46(t,J=2.3Hz,1H),3.22-3.31(m,2H),3.43-3.51(m,2H),3.56-3.64(m,2H),4.16 (d,J=2.3Hz,2H),5.07(br.s.,1H),5.10(s,2H),6.09(br.s.,1H),7.28-7.42(m,5H)；13 C NMR(100MHz，氯仿-d/TMS)δ ppm 25.9,33.7,39.1,40.5,58.3,66.7,68.7,74.8,79.4,128.1,128.5(4C),136.6,156.7,172.5；HRMS(ESI)經計算C17 H22 N2 O4 (m/z)[M+H]+ 319.1652，結果319.1646。Intermediate (Ig-1): Purification conditions: 100% ethyl acetate, quantitative, oil. 1 H NMR (400MHz, CHLOROFORM -d / TMS) δ ppm 1.80-1.91 ( m, 2H), 2.24 (t, J = 7.1Hz, 2H), 2.46 (t, J = 2.3Hz, 1H), 3.22-3.31 (m, 2H), 3.43-3.51 (m, 2H), 3.56-3.64 (m, 2H), 4.16 (d, J = 2.3 Hz, 2H), 5.07 (br.s., 1H), 5.10 (s, 2H), 6.09 (br.s., 1H), 7.28-7.42 (m, 5H); 13 C NMR (100 MHz, chloroform-d/TMS) δ ppm 25.9, 33.7, 39.1, 40.5, 58.3, 66.7, 68.7, 74.8, 79.4, 128.1, 128.5 (4C), 136.6, 156.7, 172.5; HRMS (ESI) Calculated C 17 H 22 N 2 O 4 (m/z) [M+H] + 319.1652.

中間體(I-g-2)：純化條件：70%乙酸乙酯/己烷，65mg，油(76%產率)，油。1 H NMR(400MHz，氯仿-d/TMS)δ ppm 1.79-1.91(m,2H),2.24(t,J=7.1Hz,2H),2.44(t,J=2.4Hz,2H),3.20-3.29(m,2H),3.54-3.69(m,4H),4.16(d,J=1.5Hz,4H),4.22-4.33(m,1H),5.10(br.s,3H),6.04(d,J=7.8Hz,1H),7.28-7.42(m,5H)；13 C NMR(100MHz,氯仿-d/TMS)δ ppm 25.8,33.7,40.4,48.2,58.4(2C),66.6,68.3(2C),74.7(2C),79.4(2C),128.1,128.5(4C),136.6,156.6,172.2；HRMS(ESI)經計算C21 H26 N2 O5 (m/z)[M+H]+ 387.1914，結果387.1904。Intermediate (Ig-2): Purification conditions: 70% ethyl acetate / hexanes, 65 mg, oil (76% yield), oil. 1 H NMR (400MHz, CHLOROFORM -d / TMS) δ ppm 1.79-1.91 ( m, 2H), 2.24 (t, J = 7.1Hz, 2H), 2.44 (t, J = 2.4Hz, 2H), 3.20-3.29 (m, 2H), 3.54-3.69 (m, 4H), 4.16 (d, J = 1.5 Hz, 4H), 4.22-4.33 (m, 1H), 5.10 (br.s, 3H), 6.04 (d, J = 7.8 Hz, 1H), 7.28-7.42 (m, 5H); 13 C NMR (100 MHz, chloroform-d/TMS) δ ppm 25.8, 33.7, 40.4, 48.2, 58.4 (2C), 66.6, 68.3 (2C), 74.7(2C), 79.4(2C), 128.1, 128.5(4C), 136.6, 156.6, 172.2; HRMS (ESI) calculated C 21 H 26 N 2 O 5 (m/z) [M+H] + 387.1914, Results 387.1904.

中間體(I-g-3)：純化條件：70%乙酸乙酯/己烷，42mg，油(60%產率)。1 H NMR(400MHz，氯仿-d)δ ppm 1.76-1.88(m,2H),2.21(t,J=7.1Hz,2H),2.44(t,J=2.3Hz,3H),3.18-3.30(m,2H),3.84(s,6H),4.14(d,J=2.3Hz,6H),5.10(s,2H),5.12(br.s.,1H),5.89(br.s.,1H),7.28-7.40(m,5H)；13 C NMR(100MHz，氯仿-d/TMS)δ ppm 25.7,34.3,40.3,58.6(3C),59.2,66.6,68.5(3C),74.6(3C),79.5(3C),128.1,128.5(4C),136.6,156.6,172.6； HRMS(ESI)經計算C25 H30 N2 O6 (m/z)[M+H]+ 455.2177，結果455.2167。Intermediate (Ig-3): Purification conditions: 70% ethyl acetate / hexanes, 42 mg, oil (60% yield). 1 H NMR (400MHz, CHLOROFORM -d) δ ppm 1.76-1.88 (m, 2H), 2.21 (t, J = 7.1Hz, 2H), 2.44 (t, J = 2.3Hz, 3H), 3.18-3.30 (m , 2H), 3.84 (s, 6H), 4.14 (d, J = 2.3 Hz, 6H), 5.10 (s, 2H), 5.12 (br.s., 1H), 5.89 (br.s., 1H), 7.28-7.40 (m, 5H); 13 C NMR (100 MHz, chloroform-d/TMS) δ ppm 25.7, 34.3, 40.3, 58.6 (3C), 59.2, 66.6, 68.5 (3C), 74.6 (3C), 79.5 ( 3C), 128.1, 128.5 (4C), 136.6, 156.6, 172.6; HRMS (ESI) Calculated C 25 H 30 N 2 O 6 (m/z) [M+H] + 455.2177.

中間體(I-h-1)：Intermediate (I-h-1):

令三(3-羥基丙基***基甲基)胺(THPTA；參閱文獻M.G.Finn et al.,Angewandte Chemie International Edition 48,9879(2009))(2mg,0.005毫莫耳)和硫酸銅(1mg,0.004毫莫耳)溶解於水(50微升)並隨後加入至化合物(I-e-2)(42mg,0.089毫莫耳)和炔(I-g-1)(40mg,0.125毫莫耳)之甲醇(0.9ml)溶液。隨後加入溶解於水(30微升)之抗壞血酸鈉(1.8mg,0.009毫莫耳)並令反應混合物於室溫下經攪拌24小時。蒸發溶劑並令粗產物經矽膠閃爍層析(5%至10%甲醇之二氯甲烷溶液)純化以生成呈油之所欲化合物(I-h-1)(54mg,76%產率)。[α]D 48.2(c 0.54，甲醇)；1 H NMR(400MHz，甲醇-d4 )δ ppm 1.33(s,3H),1.48(s,3H),1.70-1.83(m,2H),1.98(s,3H),2.21(t,J=7.4Hz,2H),3.13(t,J=6.9Hz,2H),3.37(t,J=5.4Hz,2H),3.51-3.70(m,14H),3.71-3.95(m,7H),4.15(t,J=6.5Hz,1H),4.29 (d,J=5.8Hz,1H),4.56(t,J=5.0Hz,2H),4.60(s,2H),5.06(s,2H),5.22(d,J=1.8Hz,1H),7.25-7.38(m,5H),8.01(s,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.7,27.0,27.4,28.5,34.4,40.5,41.4,51.6,56.7,62.4,64.9,67.5,70.0,70.5,70.8,71.1,71.5,71.6,71.65,71.7,71.73,72.6,73.8,76.2,76.5,82.1,102.4,112.4,126.1,129.0,129.1,129.6,138.6,146.1,159.0,173.6,175.7；HRMS(ESI)經計算C37 H56 N6 O13 (m/z)[M+H]+ 793.3978，結果793.3959。Tris(3-hydroxypropyltriazolylmethyl)amine (THPTA; see MG Finn et al., Angewandte Chemie International Edition 48, 9879 (2009)) (2 mg, 0.005 mmol) and copper sulfate (1 mg, 0.004 mmol) dissolved in water (50 μL) and subsequently added to the compound (Ie-2) (42 mg, 0.089 mmol) and alkyne (Ig-1) (40 mg, 0.125 mmol) of methanol (0.9) Ml) solution. Sodium ascorbate (1.8 mg, 0.009 mmol) dissolved in water (30 microliters) was then added and the reaction mixture was stirred at room temperature for 24 hours. The solvent was evaporated and the crude was purified eluting elut elut elut elut elut eluting [α] D 48.2 (c 0.54, methanol); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.33 (s, 3H), 1.48 (s, 3H), 1.70-1.83 (m, 2H), 1.98 ( s, 3H), 2.21 (t, J = 7.4 Hz, 2H), 3.13 (t, J = 6.9 Hz, 2H), 3.37 (t, J = 5.4 Hz, 2H), 3.51-3.70 (m, 14H), 3.71-3.95 (m, 7H), 4.15 (t, J = 6.5 Hz, 1H), 4.29 (d, J = 5.8 Hz, 1H), 4.56 (t, J = 5.0 Hz, 2H), 4.60 (s, 2H) ), 5.06 (s, 2H), 5.22 (d, J = 1.8 Hz, 1H), 7.25-7.38 (m, 5H), 8.01 (s, 1H); 13 C NMR (100 MHz, methanol - d 4 ) δ ppm 22.7, 27.0, 27.4, 28.5, 34.4, 40.5, 41.4, 51.6, 56.7, 62.4, 64.9, 67.5, 70.0, 70.5, 70.8, 71.1, 71.5, 71.6, 71.65, 71.7, 71.73, 72.6, 73.8, 76.2, 76.5, 82.1, 102.4, 112.4, 126.1, 129.0, 129.1, 129.6, 138.6, 146.1, 159.0, 173.6, 175.7; HRMS (ESI) calculated C 37 H 56 N 6 O 13 (m/z) [M+H] + 793.3978 The result is 793.3959.

中間體(I-h-2)：Intermediate (I-h-2):

令THPTA(22mg,0.051毫莫耳)和硫酸銅(2.5mg,0.01毫莫耳)溶解於水(70微升)並隨後加入至化合物(I-e-2)(48mg,0.1毫莫耳)和炔(I-g-2)(20mg,0.051毫莫耳)之甲醇(1ml)溶液。隨後加入溶解於水(30微升)之抗壞血酸鈉(4mg,0.02毫莫耳)並令反應混合物於室溫下經攪拌72小時。蒸發溶劑並將殘餘物置入二氯甲烷和飽和氯化銨水溶液。令水相經二氯甲烷萃取3次。令結合之有機層置於硫酸鎂上乾燥且經過濾和濃縮。該粗產物未經任何進一步純化而用於下一個步驟。THPTA (22 mg, 0.051 mmol) and copper sulfate (2.5 mg, 0.01 mmol) were dissolved in water (70 μL) and subsequently added to compound (Ie-2) (48 mg, 0.1 mmol) and alkyne (Ig-2) (20 mg, 0.051 mmol) in methanol (1 mL). Sodium ascorbate (4 mg, 0.02 mmol) dissolved in water (30 microliters) was then added and the reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated and the residue was taken into dichloromethane and saturated aqueous ammonium chloride. The aqueous phase was extracted 3 times with dichloromethane. The combined organic layers were dried over magnesium sulfate and filtered and concentrated. This crude product was used in the next step without any further purification.

中間體(I-h-3)：Intermediate (I-h-3):

令THPTA(34mg,0.079毫莫耳)和硫酸銅(4mg,0.016毫莫耳)溶解於水(200微升)並隨後加入至化合物(I- e-2)(50mg,0.1毫莫耳)和炔(I-g-3)(24mg,0.053毫莫耳)之甲醇(1ml)溶液。隨後加入溶解於水(30微升)之抗壞血酸鈉(6.5mg,0.032毫莫耳)並令反應混合物於室溫下經攪拌72小時。蒸發溶劑並將殘餘物置入二氯甲烷和飽和氯化銨水溶液。令水相經二氯甲烷萃取3次。令結合之有機層置於硫酸鎂上乾燥且經過濾和濃縮。該粗產物未經任何進一步純化而用於下一個步驟。Let THPTA (34 mg, 0.079 mmol) and copper sulfate (4 mg, 0.016 mmol) dissolve in water (200 μl) and then add to the compound (I- E-2) (50 mg, 0.1 mmol) and a solution of alkyne (I-g-3) (24 mg, 0.053 mmol) in methanol (1 ml). Sodium ascorbate (6.5 mg, 0.032 mmol) dissolved in water (30 μL) was then added and the reaction mixture was stirred at room temperature for 72 hours. The solvent was evaporated and the residue was taken into dichloromethane and saturated aqueous ammonium chloride. The aqueous phase was extracted 3 times with dichloromethane. The combined organic layers were dried over magnesium sulfate and filtered and concentrated. This crude product was used in the next step without any further purification.

縮丙酮化合物除去之一般方法：General method for removal of acetal compound:

令化合物(I-h-1)、(I-h-2)或(I-h-3)(0.030至0.068毫莫耳)溶解於乙酸、甲醇及水(分別為1.6至1.8ml,0.5ml及0.5ml)之混合物並於70℃下經攪拌24小時。蒸發溶劑並令殘餘物與甲苯共蒸發2次。令粗產物經矽膠閃爍層析純化。Compound (Ih-1), (Ih-2) or (Ih-3) (0.030 to 0.068 mmol) dissolved in a mixture of acetic acid, methanol and water (1.6 to 1.8 ml, 0.5 ml and 0.5 ml, respectively) It was stirred at 70 ° C for 24 hours. The solvent was evaporated and the residue was co- evaporated twice with toluene. The crude product was purified by silica gel flash chromatography.

實施例(4)：Example (4):

純化條件：10%甲醇之二氯甲烷溶液，43.3mg，油(85%產率)。[α]D 45(c 1，甲醇)；1 H NMR(400MHz，甲醇-d4 )δ ppm 1.72-1.83(m,2H),1.99(s,3H),2.22(t,J=7.4Hz,2H),3.13(t,J=6.8Hz,2H),3.37(t,J=5.4Hz,2H),3.52-3.79(m,20H),3.85-4.00(m,3H),4.57(t,J=5.0Hz,2H),4.61(s,2H),5.07(s,2H),5.21(s,1H),7.24-7.41(m,5H),8.02(s,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.8,27.4,34.4,40.4,41.4,51.6,56.4,64.9,67.5, 69.0,70.0,70.1,70.4,70.5,71.4,71.5(2C),71.6,71.65,71.7,72.5,84.3,102.6,126.0,129.0(2C),129.1,129.6(2C),138.6,145.8,159.0,174.0,175.8；HRMS(ESI)經計算C34 H52 N6 O13 (m/z)[M+H]+ 753.3665，結果753.3679。Purification conditions: 10% methanol in dichloromethane, 43.3 mg, oil (85% yield). [α] D 45 (c 1, methanol); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.72-1.83 (m, 2H), 1.99 (s, 3H), 2.22 (t, J = 7.4 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H), 3.37 (t, J = 5.4 Hz, 2H), 3.52-3.79 (m, 20H), 3.85-4.00 (m, 3H), 4.57 (t, J =5.0 Hz, 2H), 4.61 (s, 2H), 5.07 (s, 2H), 5.21 (s, 1H), 7.24-7.41 (m, 5H), 8.02 (s, 1H); 13 C NMR (100 MHz, Methanol-d 4 ) δ ppm 22.8, 27.4, 34.4, 40.4, 41.4, 51.6, 56.4, 64.9, 67.5, 69.0, 70.0, 70.1, 70.4, 70.5, 71.4, 71.5 (2C), 71.6, 71.65, 71.7, 72.5, 84.3, 102.6, 126.0, 129.0 (2C), 129.1, 129.6 (2C), 138.6, 145.8, 159.0, 174.0, 175.8; HRMS (ESI) calculated C 34 H 52 N 6 O 13 (m/z) [M+ H] + 753.3665, the result is 753.3679.

實施例(5)：Example (5):

純化條件：20%甲醇之二氯甲烷溶液，25mg，油(20%產率，經2步驟)。[α]D 56(c 1.25，甲醇)；1 H NMR(400MHz，甲醇-d4 )δ ppm 1.72-1.81(m,2H),1.99(s,6H),2.23(t,J=7.5Hz,2H),3.13(t,J=6.9Hz,2H),3.50-3.80(m,36H),3.85-3.91(m,6H),3.92-4.00(m,4H),4.13-4.25(m,1H),4.52-4.63(m,8H),5.07(s,2H),5.21(d,J=1.3Hz,2H),7.23-7.40(m,5H),8.01(s,2H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.6(2C),27.2,34.2,41.2,50.2,51.4(2C),56.2(2C),65.0(2C),67.3,68.8(2C),69.9(2C),70.0(2C),70.2(2C),70.3(2C),71.2(2C),71.3(4C),71.4(2C)，71.5(2C),71.52(2C),72.3(2C),84.1(2C),102.4(2C),125.8(2C),128.8(2C),128.9,129.4(2C),138.4,145.6(2C),158.8,173.8(2C),175.3；HRMS(ESI)經計算C55 H86 N10 O23 (m/z)[M+H]+ 1255.5940，結果1255.5925。Purification conditions: 20% methanol in dichloromethane, 25 mg, oil (20% yield, 2 steps). [α] D 56 (c 1.25, methanol); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.72-1.81 (m, 2H), 1.99 (s, 6H), 2.23 (t, J = 7.5 Hz, 2H), 3.13 (t, J = 6.9 Hz, 2H), 3.50-3.80 (m, 36H), 3.85-3.91 (m, 6H), 3.92-4.00 (m, 4H), 4.13-4.25 (m, 1H) , 4.52-4.63 (m, 8H), 5.07 (s, 2H), 5.21 (d, J = 1.3 Hz, 2H), 7.23-7.40 (m, 5H), 8.01 (s, 2H); 13 C NMR (100 MHz , methanol-d 4 ) δ ppm 22.6 (2C), 27.2, 34.2, 41.2, 50.2, 51.4 (2C), 56.2 (2C), 65.0 (2C), 67.3, 68.8 (2C), 69.9 (2C), 70.0 ( 2C), 70.2 (2C), 70.3 (2C), 71.2 (2C), 71.3 (4C), 71.4 (2C), 71.5 (2C), 71.52 (2C), 72.3 (2C), 84.1 (2C), 102.4 ( 2C), 125.8 (2C), 128.8 (2C), 128.9, 129.4 (2C), 138.4, 145.6 (2C), 158.8, 173.8 (2C), 175.3; HRMS (ESI) calculated C 55 H 86 N 10 O 23 (m/z) [M+H] + 1255.5940, mp. 1255.5925.

實施例(6)：Example (6):

純化條件：20%甲醇之二氯甲烷溶液，31mg，油(18%產率，經2步驟)。[α]D 53(c 1，甲醇)；1 H NMR(400 MHz，甲醇-d4 )δ ppm 1.65-1.78(m,2H),1.98(s,9H),2.19(t,J=7.3Hz,2H),3.11(t,J=6.8Hz,2H),3.51-3.80(m,54H),3.86-3.91(m,9H),3.91-3.99(m,6H),4.51-4.63(m,12H),5.06(s,2H),5.21(d,J=1.3Hz,3H),7.24-7.40(m,5H),7.98(s,3H)；HRMS(ESI)經計算C76 H120 N14 O33 (m/z)[M+2H]+ /2 879.4144，結果879.4148。Purification conditions: 20% methanol in dichloromethane, 31 mg, oil (18% yield, step 2). [α] D 53 (c 1, methanol); 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.65-1.78 (m, 2H), 1.98 (s, 9H), 2.19 (t, J = 7.3 Hz , 2H), 3.11 (t, J = 6.8 Hz, 2H), 3.51-3.80 (m, 54H), 3.86-3.91 (m, 9H), 3.91-3.99 (m, 6H), 4.51-4.63 (m, 12H) ), 5.06 (s, 2H), 5.21 (d, J = 1.3 Hz, 3H), 7.24 - 7.40 (m, 5H), 7.98 (s, 3H); HRMS (ESI) calculated C 76 H 120 N 14 O 33 (m/z) [M+2H] + /2 879.4144, yield 879.4148.

N-(2-((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)乙基)-4-胺基丁醯胺(7)、4-胺基-N-{1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]丙-2-基}丁醯胺(8)及4-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)丁醯胺(9)N-(2-(1-(1-((1S,2R,3R,4R,5S)-4-Ethylamino-2,3-dihydroxy-6,8-dioxabicyclo[3.2. 1]oct-1-yl)-2,5,8,11-tetraoxatridecane-13-yl)-1H-1,2,3-triazol-4-yl)methoxy)ethyl )-4-aminobutyrylamine (7), 4-amino-N-{1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(B) Amidino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl }-1H-1,2,3-triazol-4-yl)methoxy]propan-2-yl}butanamine (8) and 4-amino-N-(1,3-double [(1) -{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1- Base]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1- {1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl ]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl) Butylamine (9)

於圓底燒瓶中，令化合物(4)、(5)或(6)(1當量)溶解於甲醇(0.01M)並令該燒瓶經氮氣沖洗。加入Pd/C(10%,0.7當量)並令該燒瓶先後經氮氣和氫氣沖洗。令反應混合物於室溫和氫氣氛圍(使用填充氫氣之球)下經攪拌12至24小時。使用0.45微米PTFE Acrodisc Cr過濾該鈀並經甲醇輕洗1次。蒸發溶劑。In a round bottom flask, compound (4), (5) or (6) (1 equivalent) was dissolved in methanol (0.01 M) and the flask was flushed with nitrogen. Pd/C (10%, 0.7 eq.) was added and the flask was washed with nitrogen and hydrogen. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (using a hydrogen-filled ball) for 12 to 24 hours. The palladium was filtered using 0.45 micron PTFE Acrodisc Cr and lightly washed once with methanol. Evaporate the solvent.

實施例(7)：Example (7):

25.5mg，油，76%產率；[α]D 57.6(c1.25，甲醇)；1 H NMR(400MHz，甲醇-d4 )δ ppm 1.70-1.81(m,2H),1.99(s,3H),2.24(t,J=7.4Hz,2H),2.67(t,J=6.8Hz,2H),3.36-3.41(m,2H),3.51-3.80(m,19H),3.84-4.01(m,4H),4.59(t,J=5.2Hz,2H),4.61(s,2H),5.21(s,1H),8.03(s,1H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.8,29.6,34.5,40.4,42.0,51.6,56.4,64.9,69.0,70.0,70.1,70.5,70.6,71.4,71.5(2C),71.6,71.66,71.7,72.5,84.3,102.6,126.0,145.8,174.1,175.9；HRMS(ESI)經計算C26 H46 N6 O11 (m/z)[M+H]+ 619.3297，結果619.3278。25.5mg, oil, 76% yield; [α] D 57.6 (c1.25, methanol); 1 H NMR (400MHz, methanol-d 4 ) δ ppm 1.70-1.81 (m, 2H), 1.99 (s, 3H) ), 2.24 (t, J = 7.4 Hz, 2H), 2.67 (t, J = 6.8 Hz, 2H), 3.36 - 3.41 (m, 2H), 3.51-3.80 (m, 19H), 3.84 - 4.01 (m, 4H), 4.59 (t, J = 5.2 Hz, 2H), 4.61 (s, 2H), 5.21 (s, 1H), 8.03 (s, 1H); 13 C NMR (100 MHz, methanol - d 4 ) δ ppm 22.8 , 29.6, 34.5, 40.4, 42.0, 51.6, 56.4, 64.9, 69.0, 70.0, 70.1, 70.5, 70.6, 71.4, 71.5 (2C), 71.6, 71.66, 71.7, 72.5, 84.3, 102.6, 126.0, 145.8, 174.1, 175.9; HRMS (ESI) calculated C 26 H 46 N 6 O 11 (m / z) [m + H] + 619.3297, 619.3278 results.

實施例(8)：Example (8):

令粗產物溶解於甲醇/水(0.5ml,50：50)並注入HPLC管柱。使用Waters XBridge BEH C18 OBD Prep管柱(130 Å,5微米，19mm×100mm(Waters，零件編號186002978))且經線性斜率梯度流洗(17ml/分鐘流速)實施製備性高效液相層析(HPLC)。溶劑梯度：乙腈/水/三氟乙酸(2：98：0.1)至(22：58：0.1)經40分鐘。使用分析級LCMS分析所收集之分級液且令經判定具有適當純度之25.7至27.3分鐘的分級液集中並經蒸發以生成呈油之化合物(8)(10.7mg,49%產率)。[α]D 56(c 1，甲醇)；1 H NMR(500MHz，甲醇-d4 )δ ppm 1.86-1.95(m,2H),1.99(s,6H),2.37(t,J=7.0Hz,2H),2.96(t,J=7.4Hz,2H),3.50-3.80(m,36H),3.84-4.00(m,10H),4.17-4.26(m,1H),4.57-4.62(m,8H),5.21(s,2H),8.03(s,2H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.8(2C),29.2,34.5,41.8,50.4,51.6(2C),56.4(2C),65.1(2C),69.0(2C),70.1(2C),70.3(2C),70.5(2C),70.6(2C),71.4(2C),71.5(4C),71.6(2C),7.67,(2C),71.7(2C),72.5(2C),84.3(2C),102.6(2C),126.1(2C),145.8(2C),174.1(2C),175.6；HRMS(ESI)經計算C47 H80 N10 O21 (m/z)[M+H]+ 1121.5572，結果1121.5558。The crude product was dissolved in methanol/water (0.5 mL, 50:50) and poured onto a HPLC column. Preparative high performance liquid chromatography (HPLC) was performed using a Waters XBridge BEH C18 OBD Prep column (130 Å, 5 micron, 19 mm x 100 mm (Waters, part number 186002978)) and linear gradient gradient flow wash (17 ml/min flow rate). ). Solvent gradient: acetonitrile/water/trifluoroacetic acid (2:98:0.1) to (22:58:0.1) over 40 min. The fractions collected were analyzed using analytical grade LCMS and the fractions which were judged to have an appropriate purity of 25.7 to 27.3 minutes were concentrated and evaporated to give the compound (8) as oil (10.7 mg, 49% yield). [α] D 56 (c 1, methanol); 1 H NMR (500 MHz, methanol-d 4 ) δ ppm 1.86-1.95 (m, 2H), 1.99 (s, 6H), 2.37 (t, J = 7.0 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H), 3.50-3.80 (m, 36H), 3.84 - 4.00 (m, 10H), 4.17 - 4.26 (m, 1H), 4.57 - 4.62 (m, 8H) , 5.21 (s, 2H), 8.03 (s, 2H); 13 C NMR (100 MHz, methanol-d 4 ) δ ppm 22.8 (2C), 29.2, 34.5, 41.8, 50.4, 51.6 (2C), 56.4 (2C) , 65.1 (2C), 69.0 (2C), 70.1 (2C), 70.3 (2C), 70.5 (2C), 70.6 (2C), 71.4 (2C), 71.5 (4C), 71.6 (2C), 7.67, (2C ), 71.7 (2C), 72.5 (2C), 84.3 (2C), 102.6 (2C), 126.1 (2C), 145.8 (2C), 174.1 (2C), 175.6; HRMS (ESI) calculated C 47 H 80 N 10 O 21 (m/z) [M+H] + 1121.5572.

實施例(9)：Example (9):

令粗產物溶解於甲醇/水(0.5ml,50：50)並注入HPLC 管柱。使用Waters XBridge BEH C18 OBD Prep管柱(130Å,5微米，19mm×100mm(Waters，零件編號186002978))且經線性斜率梯度流洗(17ml/分鐘流速)實施製備性高效液相層析(HPLC)。溶劑梯度：乙腈/水/三氟乙酸(2：98：0.1)至(22：58：0.1)經40分鐘。使用分析級LCMS分析所收集之分級液且令經判定具有適當純度之30.3至32.0分鐘的分級液集中並經蒸發以生成呈油之化合物(9)(15mg,63%產率)。[α]D 59.1(c 1.1，甲醇)；1 H NMR(500MHz，甲醇-d4 )δ ppm 1.84-1.92(m,2H),2.00(s,9H),2.31-2.38(m,2H),2.97(t,J=7.3Hz,2H),3.54-3.80(m,54H),3.86-3.93(m,9H),3.93-4.00(m,6H),4.57(s,6H),4.60(t,J=4.9Hz,6H),5.22(s,3H),8.02(s,3H)；HRMS(ESI)經計算C68 H114 N14 O31 (m/z)[M+H]+ 1623.7847，結果1623.7803。The crude product was dissolved in methanol/water (0.5 mL, 50: 50) and poured into HPLC column. Preparative high performance liquid chromatography (HPLC) was performed using a Waters XBridge BEH C18 OBD Prep column (130 Å, 5 micron, 19 mm x 100 mm (Waters, part number 186002978)) and linear gradient gradient flow wash (17 ml/min flow rate). . Solvent gradient: acetonitrile/water/trifluoroacetic acid (2:98:0.1) to (22:58:0.1) over 40 min. The collected fractions were analyzed using analytical grade LCMS and the fractions which were judged to have an appropriate purity of 30.3 to 32.0 minutes were concentrated and evaporated to give the compound (9) as oil (15 mg, 63% yield). [α] D 59.1 (c 1.1, methanol); 1 H NMR (500 MHz, methanol-d 4 ) δ ppm 1.84-1.92 (m, 2H), 2.00 (s, 9H), 2.31-2.38 (m, 2H), 2.97 (t, J = 7.3 Hz, 2H), 3.54-3.80 (m, 54H), 3.86-3.93 (m, 9H), 3.93-4.00 (m, 6H), 4.57 (s, 6H), 4.60 (t, J = 4.9 Hz, 6H), 5.22 (s, 3H), 8.02 (s, 3H); HRMS (ESI) calculated C 68 H 114 N 14 O 31 (m/z) [M+H] + 1623.7847 1623.7803.

實施例(10)、(11)及(12)；Alexa fluor® 647共軛物Examples (10), (11) and (12); Alexa fluor® 647 conjugate

Alexa Fluor® 647羧酸琥珀醯亞胺酯係購自Invitrogen(目錄編號A-20106)。Invitrogen報告之分子量係約1250。基於由LCMS經發現之Alexa Fluor 647羧酸琥珀醯亞胺酯的[M+H]+ 為955.07，評估經該Alexa647標記之化合物分子量。消光係數λmax 650為約270000±20000，該值每批式變化。Alexa Fluor® 647 carboxylic acid amber ylide was purchased from Invitrogen (catalog number A-20106). The molecular weight reported by Invitrogen is approximately 1250. The molecular weight of the compound labeled with this Alexa647 was evaluated based on [M+H] + of 955.07 of Alexa Fluor 647 carboxylic acid amber ylide found by LCMS. The extinction coefficient λ max 650 is about 270,000 ± 20,000, which varies from batch to batch.

HPLC純化之一般方法：General method for HPLC purification:

使用Waters XBridge BEH C18 OBD Prep管柱(130Å,5微米，19mm×100mm(Waters，零件編號186002978))且經線性斜率梯度流洗(17ml/分鐘流速)實施製備性高效液相層析(HPLC)。溶劑梯度：乙腈/水/三氟乙酸(2：98：0.1)至(22：78：0.1)經40分鐘。使用分析級LCMS分析所收集之分級液且令經判定具有適當純度之分級液集中並經蒸發。Preparative high performance liquid chromatography (HPLC) was performed using a Waters XBridge BEH C18 OBD Prep column (130 Å, 5 micron, 19 mm x 100 mm (Waters, part number 186002978)) and linear gradient gradient flow wash (17 ml/min flow rate). . Solvent gradient: acetonitrile/water/trifluoroacetic acid (2:98:0.1) to (22:78:0.1) over 40 min. The collected fractions were analyzed using analytical grade LCMS and the fractions determined to have the appropriate purity were concentrated and evaporated.

實施例(10)：Example (10):

對化合物(7)(3.0mg,4.8微莫耳)之二甲亞碸(200微升)溶液加入Alexa Fluor® 647羧酸琥珀醯亞胺酯(5.0mg,4微莫耳)和N,N-二異丙基乙胺(10μl,10當量)。令反應混合物於室溫下經搖晃1小時並隨後直接經製備性HPLC純化。令所收集之分級液經分析級LCMS分析並令經判定具有適當純度之分級液集中(Rt =22.7至24分鐘)。得到化合物(10)(3.2mg,55%產率)。令溶液經等分並經真空離心蒸發且令產物儲存於4℃。MS(ESI)經計算(m/z)[M+H]+ 約1456，結果1456.82。To a solution of compound (7) (3.0 mg, 4.8 micromoles) of dimethyl hydrazine (200 μl) was added Alexa Fluor® 647 carboxylic acid amber imidate (5.0 mg, 4 micromoles) and N, N Diisopropylethylamine (10 μl, 10 equivalents). The reaction mixture was shaken at room temperature for 1 hour and then directly purified by preparative HPLC. The collected fractions were analyzed by analytical grade LCMS and concentrated to determine the appropriate purity ( Rt = 22.7 to 24 minutes). Compound (10) (3.2 mg, 55% yield) was obtained. The solution was aliquoted and evaporated by vacuum and the product was stored at 4 °C. MS (ESI) calculated (m/z) [M+H] +

實施例(11)：Example (11):

對化合物(8)(6.0mg,5微莫耳)之二甲亞碸(200微升)溶液加入Alexa Fluor® 647羧酸琥珀醯亞胺酯(5.0mg,4微莫耳)和N,N-二異丙基乙胺(10μl,10當量)。令反應混合物於室溫下經搖晃1小時並隨後直接經製備性HPLC純 化。令所收集之分級液經分析級LCMS分析並令經判定具有適當純度之分級液集中(Rt =25.3至26.7分鐘)。得到化合物(11)(4.8mg,62%產率)。令溶液經等分並經真空離心蒸發且令產物儲存於4℃。MS(ESI)經計算(m/z)[M+H]+ 約1958，結果1958.74。To a solution of compound (8) (6.0 mg, 5 micromoles) of dimethyl hydrazine (200 μl) was added Alexa Fluor® 647 carboxylic acid amber sulphate (5.0 mg, 4 micromoles) and N, N Diisopropylethylamine (10 μl, 10 equivalents). The reaction mixture was shaken at room temperature for 1 hour and then directly purified by preparative HPLC. The collected fractions were analyzed by analytical grade LCMS and concentrated to determine the appropriate purity ( Rt = 25.3 to 26.7 minutes). Compound (11) (4.8 mg, 62% yield) was obtained. The solution was aliquoted and evaporated by vacuum and the product was stored at 4 °C. MS (ESI) calculated (m/z) [M+H] + ca. 1958.

實施例(12)：Example (12):

對化合物(9)(9.8mg,6微莫耳)之二甲亞碸(200微升)溶液加入Alexa Fluor® 647羧酸琥珀醯亞胺酯(5.0mg,4.8微莫耳)和N,N-二異丙基乙胺(10μl,10當量)。令反應混合物於室溫下經搖晃1小時並隨後直接經製備性HPLC純化。令所收集之分級液經分析級LCMS分析並令經判定具有適當純度之分級液集中(Rt =27.7分鐘)。得到化合物(12)(5.2mg,52%產率)。令溶液經等分並經真空離心蒸發且令產物儲存於4℃。MS(ESI)經計算(m/z)[M+H]+ 約2460，結果2461.18。To a solution of compound (9) (9.8 mg, 6 micromoles) of dimethyl hydrazine (200 μl) was added Alexa Fluor® 647 carboxylic acid amber imidate (5.0 mg, 4.8 micromoles) and N, N Diisopropylethylamine (10 μl, 10 equivalents). The reaction mixture was shaken at room temperature for 1 hour and then directly purified by preparative HPLC. The collected fractions were analyzed by analytical grade LCMS and concentrated to determine the appropriate purity ( Rt = 27.7 minutes). Compound (12) (5.2 mg, 52% yield) was obtained. The solution was aliquoted and evaporated by vacuum and the product was stored at 4 °C. MS (ESI) calculated (m/z) [M+H] + ca. 2460.

4-胺基-N-[1,31-雙(1-{[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]甲基}-1H-1,2,3-***-4-基)-2,6,10,14,18,22,26,30-八氧雜三十一烷-16-基]丁醯胺(13)和4-胺基-N-{1,31-雙(1-{[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]甲基}-1H-1,2,3-***-4-基)-16-[15-(1-{[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]甲 基}-1H-1,2,3-***-4-基)-2,6,10,14-四氧雜十五烷-1-基]-2,6,10,14,18,22,26,30-八氧雜三十一烷-16-基}丁醯胺(14)4-Amino-N-[1,31-bis(1-{[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8- Dioxabicyclo[3.2.1]oct-1-yl]methyl}-1H-1,2,3-triazol-4-yl)-2,6,10,14,18,22,26,30 -octadecadecano-16-yl]butanamine (13) and 4-amino-N-{1,31-bis(1-{[(1S,2R,3R,4R,5S)- 4-(acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]methyl}-1H-1,2,3-triazole- 4-yl)-16-[15-(1-{[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]A }}-1H-1,2,3-triazol-4-yl)-2,6,10,14-tetraoxapentadecan-1-yl]-2,6,10,14,18,22 ,26,30-octaoxatridecane-16-yl}butanamine (14)

令化合物(I-e-1)(247mg,0.904毫莫耳)溶解於二氯甲烷(15ml)並加入吡啶(1.46ml,18.1毫莫耳)。令反應混合物冷卻至-20℃並逐滴加入三氟甲烷磺酸酐(0.23ml,1.4毫莫耳)之二氯甲烷(0.6ml)溶液且令混合物經攪拌50分鐘並同時回溫至0℃。令反應混合物經二氯甲烷稀釋並經1M氯化氫水溶液、飽和碳酸氫鈉水溶液及飽和氯化鈉水溶液沖洗。令有機相置於硫酸鎂上乾燥並經過濾和濃縮。該粗產物未經任何進一步純化而用於下一個步驟。將疊氮化鈉(270mg,4.1毫莫耳)加入至上述三氟甲磺酸酯之二甲基甲醯胺(4.1ml)溶液。令反應混合物於60℃下經攪拌16小時。蒸發溶劑並令粗產物經矽膠閃爍層析(15/1乙酸乙酯/甲醇)純化以生成呈黃色油之所欲化合物(I-e-3)(227mg,92%產率)。[α]D 127(c 1，甲醇)；1 H NMR(500MHz,氯仿-d)δ ppm 1.34(s,3H),1.53(s,3H),2.00(s,3H),3.67(d,J=12.7Hz,1H),3.72(d,J=7.8Hz,1H),3.74(d,J=7.8Hz,1H),3.75(d,J=12.7Hz,1H),4.02-4.10(m,2H),4.11(d,J=5.9Hz,1H),5.35(d,J=2.4Hz,1H),5.95(d,J=8.8Hz,1H)；13 C NMR(125MHz，氯仿-d)δ ppm 23.2,26.2,27.7,51.0,54.2,69.3,74.8,76.1,80.6,101.2,111.6, 170.1；HRMS(ESI)經計算C12 H18 N4 O5 (m/z)[M+H]+ 299.1350，結果299.1344。Compound (Ie-1) (247 mg, 0.904 mmol) was dissolved in dichloromethane (15 ml) and pyridine (1.46 ml, 18.1 mmol). The reaction mixture was cooled to -20 ° C and a solution of trifluoromethanesulfonic acid anhydride (0.23 ml, 1.4 mmol) in dichloromethane (0.6 ml) was added dropwise and the mixture was stirred for 50 min and then warmed to 0 °C. The reaction mixture was diluted with methylene chloride and washed with 1M aqueous hydrogen chloride, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and filtered and concentrated. This crude product was used in the next step without any further purification. Sodium azide (270 mg, 4.1 mmol) was added to a solution of the above trifluoromethanesulfonate in dimethylformamide (4.1 ml). The reaction mixture was allowed to stir at 60 ° C for 16 hours. The solvent was evaporated and the crude was purified EtOAcjjjjjjjjjj [α] D 127 (c 1, methanol); 1 H NMR (500 MHz, chloroform-d) δ ppm 1.34 (s, 3H), 1.53 (s, 3H), 2.00 (s, 3H), 3.67 (d, J) =12.7 Hz, 1H), 3.72 (d, J = 7.8 Hz, 1H), 3.74 (d, J = 7.8 Hz, 1H), 3.75 (d, J = 12.7 Hz, 1H), 4.02-4.10 (m, 2H) ), 4.11 (d, J = 5.9 Hz, 1H), 5.35 (d, J = 2.4 Hz, 1H), 5.95 (d, J = 8.8 Hz, 1H); 13 C NMR (125 MHz, chloroform-d) δ ppm 23.2, 26.2, 27.7, 51.0, 54.2, 69.3, 74.8, 76.1, 80.6, 101.2, 111.6, 170.1; HRMS (ESI) calculated C 12 H 18 N 4 O 5 (m/z) [M+H] + 299.1350 The result is 299.1344.

起始自3-溴丙炔和分別為化合物(I-i-2)(可購自Dalton Pharma；DC-001760)和化合物(I-i-3)(參閱文獻B.Ernst et al.,Bioorganic & Medicinal Chemistry,16,5216(2008))且隨後依循生成化合物(I-f-2)之相同方法，可製備化合物(I-j-2)和化合物(I-j-3)。Starting from 3-bromopropyne and compound (Ii-2) (available from Dalton Pharma; DC-001760) and compound (Ii-3), respectively (see B. Ernst et al., Bioorganic & Medicinal Chemistry, Compounds (Ij-2) and (Ij-3) can be produced in the same manner as in the production of the compound (If-2), and then in the same manner as in the production of the compound (If-2).

化合物(I-j-2)：純化條件：20%乙酸乙酯/己烷；85mg；油(8%產率)；1 H NMR(400MHz，氯仿-d/TMS)δ ppm 1.77-1.90(m,14H),2.23(t,J=7.1Hz,2H),2.43(t,J=2.3Hz,2H),3.20-3.29(m,2H),3.39-3.55(m,24H),3.60(t,J=6.3Hz,4H),4.13(d,J=2.5Hz,4H),4.15-4.24(m,1H),5.09(s,2H),5.16(br.s.,1H),6.05(d,J=8.1Hz,1H),7.28-7.41(m,5H)；13 C NMR(100MHz，氯仿-d/TMS)δ ppm 25.8,29.8(2C),29.9(2C),30.0(2C),33.7,40.4,48.5,58.1(2C),66.6,67.2(2C),67.6(2C),67.7(2C),67.8(2C),67.9(2C),68.3(2C),69.0(2C),74.2(2C),79.9(2C),128.1,128.5(4C),136.6,156.6,172.1；HRMS(ESI)經計算C39 H62 N2 O11 (m/z)[M+H]+ 735.4426，結果735.4424。Compound (Ij-2): Purification conditions: 20% ethyl acetate / hexane; 85 mg; oil (8% yield); 1 H NMR (400 MHz, chloroform-d/TMS) δ ppm 1.77-1.90 (m, 14H) ), 2.23 (t, J = 7.1 Hz, 2H), 2.43 (t, J = 2.3 Hz, 2H), 3.20-3.29 (m, 2H), 3.39-3.55 (m, 24H), 3.60 (t, J = 6.3 Hz, 4H), 4.13 (d, J = 2.5 Hz, 4H), 4.15-4.24 (m, 1H), 5.09 (s, 2H), 5.16 (br.s., 1H), 6.05 (d, J = 8.1 Hz, 1H), 7.28-7.41 (m, 5H); 13 C NMR (100 MHz, chloroform-d/TMS) δ ppm 25.8, 29.8 (2C), 29.9 (2C), 30.0 (2C), 33.7, 40.4, 48.5,58.1(2C),66.6,67.2(2C),67.6(2C),67.7(2C),67.8(2C),67.9(2C),68.3(2C),69.0(2C),74.2(2C),79.9 (2C), 128.1, 128.5 (4C), 136.6, 156.6, 172.1; HRMS (ESI) Calculated C 39 H 62 N 2 O 11 (m/z) [M+H] + 735.4426.

化合物(I-j-3)：純化條件：85%乙酸乙酯/己烷；32.6mg；油(71%產率)；1 H NMR(400MHz，氯仿-d/TMS)δ ppm 1.75-1.90(m,20H),2.18(t,J=6.9Hz,2H),2.43(t, J=2.4Hz,3H),3.23(q,J=6.3Hz,2H),3.40-3.53(m,30H),3.59(t,J=6.3Hz,6H),3.67(s,6H),4.13(d,J=2.3Hz,6H),5.08(s,2H),5.27(br.s.,1H),5.85(s,1H),7.27-7.40(m,5H)；13 C NMR(100MHz，氯仿-d/TMS)δ ppm 25.7,29.7(3C),29.9(3C),30.0(3C),34.4,40.4,58.1(3C),59.8,66.5,67.1(3C),67.6(3C),67.7(3C),67.8(3C),67.82(3C),68.4(3C),69.1(3C),74.2(3C),79.9(3C),128.0,128.4(4C),136.6,156.6,172.3；HRMS(ESI)經計算C52 H84 N2 O15 (m/z)[M+H]+ 977.5944，結果977.5943。Compound (Ij-3): purification conditions: 85% ethyl acetate / hexane; 32.6 mg; oil (71% yield); 1 H NMR (400 MHz, chloroform-d/TMS) δ ppm 1.75-1.90 (m, 20H), 2.18 (t, J = 6.9 Hz, 2H), 2.43 (t, J = 2.4 Hz, 3H), 3.23 (q, J = 6.3 Hz, 2H), 3.40 - 3.53 (m, 30H), 3.59 ( t, J = 6.3 Hz, 6H), 3.67 (s, 6H), 4.13 (d, J = 2.3 Hz, 6H), 5.08 (s, 2H), 5.27 (br.s., 1H), 5.85 (s, 1H), 7.27-7.40 (m, 5H); 13 C NMR (100MHz, chloroform-d/TMS) δ ppm 25.7, 29.7 (3C), 29.9 (3C), 30.0 (3C), 34.4, 40.4, 58.1 (3C ), 59.8, 66.5, 67.1 (3C), 67.6 (3C), 67.7 (3C), 67.8 (3C), 67.82 (3C), 68.4 (3C), 69.1 (3C), 74.2 (3C), 79.9 (3C) , 128.0, 128.4 (4C), 136.6, 156.6, 172.3; HRMS (ESI) Calculated C 52 H 84 N 2 O 15 (m/z) [M+H] + 977.5944.

化合物(I-k-2)：Compound (I-k-2):

令THPTA(22.6mg,0.052毫莫耳)和硫酸銅(2.5mg,0.01毫莫耳)溶解於水(200微升)並隨後加入至化合物(I-e-3)(45mg,0.152毫莫耳)和化合物(I-j-2)(51mg,0.069毫莫耳)之甲醇(1.1ml)溶液。隨後加入溶解於水(100微升)之抗壞血酸鈉(4.2mg,0.021毫莫耳)並令反應混合物於50℃下經攪拌24小時。蒸發溶劑並令粗產物經矽膠閃爍層析(5%甲醇之二氯甲烷溶液)純化以生成呈油之所欲化合物(I-k-2)(72mg,78%產率)。1 H NMR(400MHz，甲醇-d4 )δ ppm 1.34(s,6H),1.52(s,6H),1.73-1.86(m,12H),1.97(s,6H),2.24(t,J=7.4Hz,2H),3.15(t,J=6.8Hz,2H),3.43- 3.54(m,22H),3.58(t,J=6.3Hz,4H),3.86(d,J=8.1Hz,2H),3.97(dd,J=6.2,1.9Hz,2H),4.11-4.23(m,5H),4.58(s,4H),4.78(s,6H),4.91(d,J=14.1Hz,2H),4.98(d,J=14.4Hz,2H),5.07(s,2H),5.24(d,J=1.8Hz,2H),7.25-7.40(m,5H),7.99(s,2H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.7(2C),26.8(2C),27.5,28.4(2C),31.1(4C),31.2(2C),34.5,41.4,50.6,51.0(2C),56.3(2C),64.8(2C),67.5(2C),68.7(2C),68.8(2C),68.9(3C),69.0(2C),69.4(2C),69.7(2C),70.9(2C),76.3(2C),76.6(2C),81.5(2C),102.5(2C),112.8(2C),127.2(2C),129.0(2C),129.1,129.6(2C),138.6,146.3(2C),159.0,173.5(2C),175.5；HRMS(ESI)經計算C63 H98 N10 O21 (m/z)[M+H]+ 1331.6981，結果1331.6971。THPTA (22.6 mg, 0.052 mmol) and copper sulfate (2.5 mg, 0.01 mmol) were dissolved in water (200 μL) and subsequently added to compound (Ie-3) (45 mg, 0.152 mmol) and A solution of compound (Ij-2) (51 mg, 0.069 mmol) in methanol (1.1 mL). Sodium ascorbate (4.2 mg, 0.021 mmol) dissolved in water (100 μL) was then added and the reaction mixture was stirred at 50 ° C for 24 hours. The solvent was evaporated and the crude was purified EtOAcjjjjjjjjjj 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 1.34 (s, 6H), 1.52 (s, 6H), 1.73-1.86 (m, 12H), 1.97 (s, 6H), 2.24 (t, J = 7.4 Hz, 2H), 3.15 (t, J = 6.8 Hz, 2H), 3.43 - 3.54 (m, 22H), 3.58 (t, J = 6.3 Hz, 4H), 3.86 (d, J = 8.1 Hz, 2H), 3.97 (dd, J=6.2, 1.9 Hz, 2H), 4.11-4.23 (m, 5H), 4.58 (s, 4H), 4.78 (s, 6H), 4.91 (d, J = 14.1 Hz, 2H), 4.98 (d, J = 14.4 Hz, 2H), 5.07 (s, 2H), 5.24 (d, J = 1.8 Hz, 2H), 7.25-7.40 (m, 5H), 7.99 (s, 2H); 13 C NMR ( 100MHz, methanol-d 4 ) δ ppm 22.7 (2C), 26.8 (2C), 27.5, 28.4 (2C), 31.1 (4C), 31.2 (2C), 34.5, 41.4, 50.6, 51.0 (2C), 56.3 (2C) ), 64.8 (2C), 67.5 (2C), 68.7 (2C), 68.8 (2C), 68.9 (3C), 69.0 (2C), 69.4 (2C), 69.7 (2C), 70.9 (2C), 76.3 (2C) ), 76.6 (2C), 81.5 (2C), 102.5 (2C), 112.8 (2C), 127.2 (2C), 129.0 (2C), 129.1, 129.6 (2C), 138.6, 146.3 (2C), 159.0, 173.5 ( 2C), 175.5; HRMS (ESI ) calculated C 63 H 98 N 10 O 21 (m / z) [m + H] + 1331.6981, 1331.6971 results.

化合物(I-k-3)：Compound (I-k-3):

令THPTA(16mg,0.037毫莫耳)和硫酸銅(1.7mg,0.007毫莫耳)溶解於水(100微升)並隨後加入至化合物(I-e-3)(32.5mg,0.109毫莫耳)和化合物(I-j-3)(32mg,0.033毫莫耳)之甲醇(1.1ml)溶液。隨後加入溶解於水(100微升)之抗壞血酸鈉(3mg,0.015毫莫耳)並令反應混合物於50℃下經攪拌24小時。蒸發溶劑並令粗產物經矽膠閃爍層析(10%甲醇之二氯甲烷溶液)純化以生成呈油之所欲化合物(I-k-3)(43.5mg,70%產率)。1 H NMR(400MHz，甲醇-d4 )δ ppm 1.33(s,9H),1.52(s,9H),1.71-1.87(m,18H), 1.97(s,9H),2.20(t,J=7.3Hz,2H),3.15(t,J=6.8Hz,2H),3.43-3.52(m,28H),3.58(t,J=6.3Hz,6H),3.67(s,6H),3.86(d,J=8.3Hz,3H),3.97(dd,J=6.0,1.8Hz,3H),4.14-4.22(m,5H),4.58(s,6H),4.78(s,8H),4.91(d,J=14.6Hz,3H),4.97(d,J=14.6Hz,3H),5.07(s,2H),5.24(d,J=2.0Hz,3H),7.26-7.38(m,5H),7.98(s,3H)；13 C NMR(100MHz，甲醇-d4 )δ ppm 22.7(3C),26.9(3C),27.7,28.4(3C),31.1(3C),31.2(3C),31.3(3C),35.2,41.3,51.0(3C),56.3(3C),61.8,64.9(3C),67.5(3C),68.7(3C),68.8(3C),68.9(3C),69.0(4C),69.6(3C),69.7(3C),70.0(3C),76.3(3C),76.6(3C),81.5(3C),102.5(3C),112.8(3C),127.2(3C),129.0(2C),129.1,129.7(2C),138.6,146.4(3C),159.0,173.5(3C),175.6；HRMS(ESI)經計算C88 H138 N14 O30 (m/z)[M+H]+ 1871.9776，結果1871.9713。THPTA (16 mg, 0.037 mmol) and copper sulfate (1.7 mg, 0.007 mmol) were dissolved in water (100 μL) and subsequently added to compound (Ie-3) (32.5 mg, 0.109 mmol) and A solution of compound (Ij-3) (32 mg, 0.033 mmol) in methanol (1.1 mL). Sodium ascorbate (3 mg, 0.015 mmol) dissolved in water (100 microliters) was then added and the reaction mixture was stirred at 50 °C for 24 hours. The solvent was evaporated and the crude was purified EtOAcjjjjjjjjj 1 H NMR (400MHz, methanol -d 4) δ ppm 1.33 (s , 9H), 1.52 (s, 9H), 1.71-1.87 (m, 18H), 1.97 (s, 9H), 2.20 (t, J = 7.3 Hz, 2H), 3.15 (t, J = 6.8 Hz, 2H), 3.43 - 3.52 (m, 28H), 3.58 (t, J = 6.3 Hz, 6H), 3.67 (s, 6H), 3.86 (d, J) = 8.3 Hz, 3H), 3.97 (dd, J = 6.0, 1.8 Hz, 3H), 4.14 - 4.22 (m, 5H), 4.58 (s, 6H), 4.78 (s, 8H), 4.91 (d, J = 14.6 Hz, 3H), 4.97 (d, J = 14.6 Hz, 3H), 5.07 (s, 2H), 5.24 (d, J = 2.0 Hz, 3H), 7.26-7.38 (m, 5H), 7.98 (s, 3H); 13 C NMR (100MHz, methanol-d 4 ) δ ppm 22.7 (3C), 26.9 (3C), 27.7, 28.4 (3C), 31.1 (3C), 31.2 (3C), 31.3 (3C), 35.2, 41.3, 51.0 (3C), 56.3 (3C), 61.8, 64.9 (3C), 67.5 (3C), 68.7 (3C), 68.8 (3C), 68.9 (3C), 69.0 (4C), 69.6 (3C), 69.7 (3C), 70.0 (3C), 76.3 (3C), 76.6 (3C), 81.5 (3C), 102.5 (3C), 112.8 (3C), 127.2 (3C), 129.0 (2C), 129.1, 129.7 (2C) , 138.6, 146.4 (3C), 159.0, 173.5 (3C), 175.6; HRMS (ESI) Calculated C 88 H 138 N 14 O 30 (m/z) [M+H] + 1871.9776, 1871.9713.

令化合物(I-k-2)或化合物(I-k-3)(0.068毫莫耳)溶解於乙酸、甲醇及水(分別為2.5至3ml、0.6至0.9ml及0.6至0.9ml)之混合物並於70℃下經攪拌24小時。蒸發溶劑並令殘餘物與甲苯共蒸發2次。所得之粗產物未經任何進一步純化而用於下一個步驟。Compound (Ik-2) or compound (Ik-3) (0.068 mmol) is dissolved in a mixture of acetic acid, methanol and water (2.5 to 3 ml, 0.6 to 0.9 ml and 0.6 to 0.9 ml, respectively) at 70 ° C It was stirred for 24 hours. The solvent was evaporated and the residue was co- evaporated twice with toluene. The crude product obtained was used in the next step without any further purification.

於圓底燒瓶中，令化合物(I-l-2)或化合物(I-l-3)(1當量)溶解於甲醇(0.01M)並令該燒瓶經氮氣沖洗。加入Pd/C(10%,0.7當量)並令該燒瓶先後經氮氣和氫氣沖洗。令反應混合物於室溫和氫氣氛圍(使用氫氣瓶)下經攪拌24小時。使用0.45微米PTFE Acrodisc Cr過濾鈀並經甲醇輕洗1次。蒸發溶劑。In a round bottom flask, Compound (I-1-2) or Compound (I-1-3) (1 equivalent) was dissolved in methanol (0.01 M) and the flask was flushed with nitrogen. Pd/C (10%, 0.7 eq.) was added and the flask was washed with nitrogen and hydrogen. The reaction mixture was allowed to stir at room temperature under a hydrogen atmosphere (using a hydrogen gas) for 24 hours. The palladium was filtered using 0.45 micron PTFE Acrodisc Cr and lightly washed once with methanol. Evaporate the solvent.

實施例(13)：Example (13):

令粗產物溶解於甲醇/水(0.5ml,50：50)並注入HPLC管柱。使用Waters XBridge BEH C18 OBD Prep管柱(130Å,5微米，19mm×100mm(Waters，零件編號186002978))且經線性斜率梯度流洗(17ml/分鐘流速)實施製備性高效液相層析(HPLC)。溶劑梯度：乙腈/水/三氟乙酸(2：98：0.1)至(22：58：0.1)經40分鐘。使用分析級LCMS分析所收集之分級液且令經判定具有適當純度之34.7至35.6分鐘的分級液集中並經蒸發以生成呈油之化合物(13)(12.8mg,17%產率，經2步驟)。1 H NMR(500MHz，甲醇-d4 )δ ppm 1.73-1.87(m,12H),1.88-1.96(m,2H),1.98(s,6H),2.39(t,J=7.0Hz,2H),2.98(t,J=7.4Hz,2H),3.42(d,J=8.5Hz,2H),3.45-3.55(m,24H),3.59(t,J=6.3Hz,4H),3.71-3.75(m,4H),3.77(d,J=8.3Hz,2H),3.96-4.02(m,2H),4.13-4.20(m,1H),4.58(s,4H),4.91-4.95(m,4H),5.20(d,J=1.5Hz,2H),7.98(s,2H)；HRMS(ESI)經計算C49 H84 N10 O19 (m/z)[M+H]+ 1117.5987，結果1117.5977。The crude product was dissolved in methanol/water (0.5 mL, 50:50) and poured onto a HPLC column. Preparative high performance liquid chromatography (HPLC) was performed using a Waters XBridge BEH C18 OBD Prep column (130 Å, 5 micron, 19 mm x 100 mm (Waters, part number 186002978)) and linear gradient gradient flow wash (17 ml/min flow rate). . Solvent gradient: acetonitrile/water/trifluoroacetic acid (2:98:0.1) to (22:58:0.1) over 40 min. The fractionated liquid collected was analyzed using analytical grade LCMS and the fractionated liquid which was judged to have an appropriate purity of 34.7 to 35.6 minutes was concentrated and evaporated to give the compound (13) as oil (12.8 mg, 17% yield, in 2 steps ). 1 H NMR (500MHz, methanol -d 4) δ ppm 1.73-1.87 (m , 12H), 1.88-1.96 (m, 2H), 1.98 (s, 6H), 2.39 (t, J = 7.0Hz, 2H), 2.98 (t, J = 7.4 Hz, 2H), 3.42 (d, J = 8.5 Hz, 2H), 3.45-3.55 (m, 24H), 3.59 (t, J = 6.3 Hz, 4H), 3.71-3.75 (m) , 4H), 3.77 (d, J = 8.3 Hz, 2H), 3.96-4.02 (m, 2H), 4.13-4.20 (m, 1H), 4.58 (s, 4H), 4.91-4.95 (m, 4H), 5.20 (d, J = 1.5 Hz, 2H), 7.98 (s, 2H); HRMS (ESI) Calculated C 49 H 84 N 10 O 19 (m/z) [M+H] + 1117.5987

實施例(14)：Example (14):

令粗產物溶解於甲醇/水(0.5ml,50：50)並注入HPLC管柱。使用Waters XBridge BEH C18 OBD Prep管柱(130Å,5微米，19mm×100mm(Waters，零件編號186002978))且經線性斜率梯度流洗(17ml/分鐘流速)實施製備性高效液相層析(HPLC)。溶劑梯度：乙腈/水/三氟乙酸(2：98：0.1)至(42：58：0.1)經40分鐘。使用分析級LCMS分析所收集之分級液且令經判定具有適當純度之24.7至25.6分鐘的分級液集中並經蒸發以生成呈油之化合物(14)(5.5mg,10%產率，經2步驟)。1 H NMR(500MHz，甲醇-d4 )δ ppm 1.75-1.86(m,18H),1.87-1.94(m,2H),1.98(s,9H),2.37(t,J=6.8Hz,2H),2.98(t,J=7.4Hz,2H),3.43(d,J=8.5Hz,3H),3.46-3.53(m,31H),3.59(t,J=6.3Hz,6H),3.68(s,6H),3.72-3.76(m,5H),3.77(d,J=8.3Hz,3H),3.97-4.02(m,3H),4.59(s,6H),4.90-4.96(m,6H),5.20(d,J=1.2Hz,3H)7.98(s,3H)；HRMS(ESI)經計算C71 H120 N14 O28 (m/z)[M+H]+ 1617.8469，結果1617.8415。The crude product was dissolved in methanol/water (0.5 mL, 50:50) and poured onto a HPLC column. Preparative high performance liquid chromatography (HPLC) was performed using a Waters XBridge BEH C18 OBD Prep column (130 Å, 5 micron, 19 mm x 100 mm (Waters, part number 186002978)) and linear gradient gradient flow wash (17 ml/min flow rate). . Solvent gradient: acetonitrile / water / trifluoroacetic acid (2: 98: 0.1) to (42: 58: 0.1) over 40 min. The collected fractions were analyzed using analytical grade LCMS and the fractions which were judged to have an appropriate purity of 24.7 to 25.6 minutes were concentrated and evaporated to give the compound (14) as oil (5.5 mg, 10% yield, in 2 steps ). 1 H NMR (500MHz, methanol -d 4) δ ppm 1.75-1.86 (m , 18H), 1.87-1.94 (m, 2H), 1.98 (s, 9H), 2.37 (t, J = 6.8Hz, 2H), 2.98 (t, J = 7.4 Hz, 2H), 3.43 (d, J = 8.5 Hz, 3H), 3.46-3.53 (m, 31H), 3.59 (t, J = 6.3 Hz, 6H), 3.68 (s, 6H) ), 3.72-3.76 (m, 5H), 3.77 (d, J = 8.3 Hz, 3H), 3.97-4.02 (m, 3H), 4.59 (s, 6H), 4.90-4.96 (m, 6H), 5.20 ( d, J = 1.2 Hz, 3H) 7.98 (s, 3H); HRMS (ESI) calculated C 71 H 120 N 14 O 28 (m/z) [M+H] + 1617.8469, 1617.8415.

實施例(15)和(16)；Alexa fluor® 647(AF647)共軛物Examples (15) and (16); Alexa fluor® 647 (AF647) conjugate

Alexa Fluor® 647羧酸琥珀醯亞胺酯係購自Invitrogen(目錄編號A-20106)。Invitrogen報告之分子量 係約1250。基於由LCMS經發現之Alexa Fluor 647羧酸琥珀醯亞胺酯的[M+H]+ 為955.07，評估經該Alexa647標記之化合物分子量。消光係數λmax 650為約270000±20000，該值每批式變化。Alexa Fluor® 647 carboxylic acid amber ylide was purchased from Invitrogen (catalog number A-20106). The molecular weight reported by Invitrogen is approximately 1250. The molecular weight of the compound labeled with this Alexa647 was evaluated based on [M+H] + of 955.07 of Alexa Fluor 647 carboxylic acid amber ylide found by LCMS. The extinction coefficient λ max 650 is about 270,000 ± 20,000, which varies from batch to batch.

HPLC純化之一般方法：General method for HPLC purification:

使用Waters XBridge BEH C18 OBD Prep管柱(130Å,5微米，19mm×100mm(Waters，零件編號186002978))且經線性斜率梯度流洗(17ml/分鐘流速)實施製備性高效液相層析(HPLC)。溶劑梯度：乙腈/水/三氟乙酸(2：98：0.1)至(22：78：0.1)經40分鐘。使用分析級LCMS分析所收集之分級液且令經判定具有適當純度之分級液集中並經蒸發。Preparative high performance liquid chromatography (HPLC) was performed using a Waters XBridge BEH C18 OBD Prep column (130 Å, 5 micron, 19 mm x 100 mm (Waters, part number 186002978)) and linear gradient gradient flow wash (17 ml/min flow rate). . Solvent gradient: acetonitrile/water/trifluoroacetic acid (2:98:0.1) to (22:78:0.1) over 40 min. The collected fractions were analyzed using analytical grade LCMS and the fractions determined to have the appropriate purity were concentrated and evaporated.

實施例(15)：Example (15):

對化合物(13)(4.5mg,4微莫耳)之二甲亞碸(200微升)溶液加入Alexa Fluor® 647羧酸琥珀醯亞胺酯(5.0mg,4微莫耳)和N,N-二異丙基乙胺(10μl,10當量)。令反應混合物於室溫下經搖晃1小時並隨後直接經製備性HPLC純化。令所收集之分級液經分析級LCMS分析並令經判定具有適當純度之分級液集中(Rt =37.3至39分鐘)。得到化合物(15)(4.0mg,50%產率)。令溶液經等分並經真空離心蒸發且令產物儲存於4℃。MS(ESI)經計算(m/z)[M+H]+ 約1955，結果1955.32。To a solution of compound (13) (4.5 mg, 4 micromoles) of dimethyl hydrazine (200 μl) was added Alexa Fluor® 647 carboxylic acid amber imidate (5.0 mg, 4 micromoles) and N, N Diisopropylethylamine (10 μl, 10 equivalents). The reaction mixture was shaken at room temperature for 1 hour and then directly purified by preparative HPLC. The collected fractions were analyzed by analytical grade LCMS and concentrated to determine the appropriate purity ( Rt = 37.3 to 39 minutes). Compound (15) (4.0 mg, 50% yield) was obtained. The solution was aliquoted and evaporated by vacuum and the product was stored at 4 °C. MS (ESI) calculated (m/z) [M+H] + </ RTI>< / RTI>

實施例(16)：Example (16):

對化合物(14)(5.2mg,3.2微莫耳)之二甲亞碸(200微升)溶液加入Alexa Fluor® 647羧酸琥珀醯亞胺酯(5.0mg,4微莫耳)和N,N-二異丙基乙胺(10μl,10當量)。令反應混合物於室溫下經搖晃1小時並隨後直接經製備性HPLC純化。令所收集之分級液經分析級LCMS分析並令經判定具有適當純度之分級液集中(Rt =24.3至25.3分鐘)。得到化合物(16)(4.0mg,51%產率)。令溶液經等分並經真空離心蒸發且令產物儲存於4℃。MS(ESI)經計算(m/z)[M+H]+ 約2455，結果2456.90。To a solution of compound (14) (5.2 mg, 3.2 micromoles) of dimethyl hydrazine (200 μl) was added Alexa Fluor® 647 carboxylic acid amber imidate (5.0 mg, 4 micromoles) and N, N Diisopropylethylamine (10 μl, 10 equivalents). The reaction mixture was shaken at room temperature for 1 hour and then directly purified by preparative HPLC. The collected fractions were analyzed by analytical grade LCMS and concentrated to determine the appropriate purity ( Rt = 24.3 to 25.3 minutes). Compound (16) (4.0 mg, 51% yield) was obtained. The solution was aliquoted and evaporated by vacuum and the product was stored at 4 °C. MS (ESI) calculated (m/z) [M+H] + ca. 2455.

實施實施例(17)至(21)之一般烷基化/去保護反應條件：General alkylation/deprotection reaction conditions for carrying out Examples (17) to (21):

對化合物(I-e-1)之二氯甲烷溶液加入所欲之碘烷基硫酸氫四丁基銨和12.5M氫氧化鈉水溶液。令反應混合物於室溫下經隔夜攪拌，經水和二氯甲烷稀釋並令水相再經二氯甲烷萃取2次。令結合之有機層經1M氫氯酸水溶液和水沖洗，置於硫酸鎂上乾燥並經過濾和減壓下濃縮。所生成之粗產物可進入下一個反應或經矽膠閃爍層析純化。令所生成之產物溶解於乙酸/甲醇/水(3：1：1 v/v)混合物並令溶液經隔夜加熱至60至70℃。令反應混合物於減壓下經濃縮並與甲苯共蒸發2次且令粗產物經矽膠閃爍層析或逆相層析純化。To the dichloromethane solution of the compound (I-e-1), a desired tetraethylammonium iodide hydrogen sulfate solution and a 12.5 M aqueous sodium hydroxide solution were added. The reaction mixture was stirred overnight at room temperature, diluted with water and dichloromethane and brine and then twice The combined organic layers were washed with 1M aq. EtOAc and water and dried over magnesium sulfate. The resulting crude product can be passed to the next reaction or purified by silica gel scintillation chromatography. The resulting product was dissolved in an acetic acid/methanol/water (3:1:1 v/v) mixture and the solution was heated overnight to 60 to 70 °C. The reaction mixture was concentrated under reduced pressure and co-evaporated twice with toluene and the crude product was purified by silica gel chromatography or reverse phase chromatography.

N-[(1S,2R,3R,4R,5S)-1-(乙氧基甲基)-2,3-二羥基-6,8-二氧 雜雙環[3.2.1]辛-4-基]乙醯胺(17)N-[(1S,2R,3R,4R,5S)-1-(ethoxymethyl)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-4-yl]acetamidamine (17)

如上述之一般方法，使用碘乙烷(20當量)，合成化合物(17)。令粗產物溶解於甲醇並加入活化炭。令混合物經攪拌15分鐘並經過濾和減壓下濃縮。令粗產物經矽膠閃爍層析(乙酸乙酯/甲醇(15：1)洗提)純化。收集含有所欲之產物的分級液並經減壓下濃縮。對粗產物加入乙酸乙酯/甲醇(15：1)以產生沉澱物，該沉澱物經過濾以生成呈固體之所欲產物(9.1mg,32%產率)。1 H NMR(400MHz，甲醇-d4 )δ ppm 5.23(d,J=1.5Hz,1H),3.97(dd,J=9.7,1.4Hz,1H),3.94(d,J=9.3Hz,1H),3.88(d,J=4.3Hz,1H),3.79(d,J=8.1Hz,1H),3.73(dd,J=9.8,4.3Hz,1H),3.66(d,J=8.1Hz,1H),3.60(d,J=9.6Hz,1H),3.59(dq,J=9.6,7.1Hz,1H),3.55(dq,J=9.6,7.1Hz,1H),2.00(s,3H),1.19(t,J=6.9Hz,3H)。LCMS(APCI)m/z：262.1[M+H](100%)。The compound (17) was synthesized by the usual method described above using ethyl iodide (20 equivalents). The crude product was dissolved in methanol and activated carbon was added. The mixture was stirred for 15 min and filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography eluting with ethyl acetate / methanol (15:1). A fraction containing the desired product was collected and concentrated under reduced pressure. Ethyl acetate/methanol (15:1) was added to the crude product to give a precipitate which was filtered to give the desired product as a solid (9.1 mg, 32% yield). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 5.23 (d, J = 1.5 Hz, 1H), 3.97 (dd, J = 9.7, 1.4 Hz, 1H), 3.94 (d, J = 9.3 Hz, 1H) , 3.88 (d, J = 4.3 Hz, 1H), 3.79 (d, J = 8.1 Hz, 1H), 3.73 (dd, J = 9.8, 4.3 Hz, 1H), 3.66 (d, J = 8.1 Hz, 1H) , 3.60 (d, J = 9.6 Hz, 1H), 3.59 (dq, J = 9.6, 7.1 Hz, 1H), 3.55 (dq, J = 9.6, 7.1 Hz, 1H), 2.00 (s, 3H), 1.19 ( t, J = 6.9 Hz, 3H). LCMS (APCI) m/z: 2621. [M+H] (100%).

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(丙氧基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(18)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(propoxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl Acetamine (18)

如上述之一般方法，使用碘丙烷(20當量)，合成化合 物(18)。令粗產物經矽膠閃爍層析(乙酸乙酯/甲醇(15：2)洗提)純化以生成呈油之所欲產物(13.9mg,80%產率)。1 H NMR(400MHz，甲醇-d4 )δ ppm 5.23(d,J=1.5Hz,1H),3.97(dd,J=9.7,1.4Hz,1H),3.95(d,J=9.6Hz,1H),3.89(d,J=4.3Hz,1H),3.79(d,J=7.8Hz,1H),3.73(dd,J=9.8,4.3Hz,1H),3.66(d,J=8.1Hz,1H),3.59(d,J=9.3Hz,1H),3.49(dt,J=9.3,6.5Hz,1H),3.46(dt,J=9.3,6.5Hz,1H),2.01(s,3H),1.60(qt,J=7.4,6.5Hz,2H),0.94(t,J=7.4Hz,3H)。LCMS(APCI)m/z：276.2[M+H](100%)。The compound (18) was synthesized by the usual method described above using iodopropane (20 equivalents). The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 5.23 (d, J = 1.5 Hz, 1H), 3.97 (dd, J = 9.7, 1.4 Hz, 1H), 3.95 (d, J = 9.6 Hz, 1H) , 3.89 (d, J = 4.3 Hz, 1H), 3.79 (d, J = 7.8 Hz, 1H), 3.73 (dd, J = 9.8, 4.3 Hz, 1H), 3.66 (d, J = 8.1 Hz, 1H) , 3.59 (d, J = 9.3 Hz, 1H), 3.49 (dt, J = 9.3, 6.5 Hz, 1H), 3.46 (dt, J = 9.3, 6.5 Hz, 1H), 2.01 (s, 3H), 1.60 ( Qt, J = 7.4, 6.5 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). LCMS (APCI) m/z: 276.2 [M+H] (100%).

N-[(1S,2R,3R,4R,5S)-1-(丁氧基甲基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(19)N-[(1S,2R,3R,4R,5S)-1-(butoxymethyl)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-4-yl Acetamine (19)

如上述之一般方法，使用碘丁烷(20當量)，合成化合物(19)。令所欲粗產物經矽膠閃爍層析(乙酸乙酯/甲醇(15：1)洗提)純化以生成呈油之所欲產物(18mg,100%產率)。1 H NMR(400MHz，甲醇-d4 )δ ppm 5.23(d,J=1.3Hz,1H),3.97(dd,J=9.6,1.3Hz,1H),3.94(d,J=9.6Hz,1H),3.88(d,J=4.3Hz,1H),3.79(d,J=7.8Hz,1H),3.73(dd,J=9.8,4.3Hz,1H),3.66(d,J=7.8Hz,1H),3.59(d,J=9.3Hz,1H),3.54(dt,J=9.3,6.5Hz,1H),3.50(dt,J=9.3,6.5Hz,1H),2.00(s,3H),1.52-1.61(m,2H),1.34- 1.45(m,2 H),0.95(t,J=7.3Hz,3H)。LCMS(APCI)m/z：290.2[M+H](100%)。The compound (19) was synthesized by the usual method described above using iodine (20 equivalents). The desired crude product was purified by EtOAc EtOAc (EtOAc) elute 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 5.23 (d, J = 1.3 Hz, 1H), 3.97 (dd, J = 9.6, 1.3 Hz, 1H), 3.94 (d, J = 9.6 Hz, 1H) , 3.88 (d, J = 4.3 Hz, 1H), 3.79 (d, J = 7.8 Hz, 1H), 3.73 (dd, J = 9.8, 4.3 Hz, 1H), 3.66 (d, J = 7.8 Hz, 1H) , 3.59 (d, J = 9.3 Hz, 1H), 3.54 (dt, J = 9.3, 6.5 Hz, 1H), 3.50 (dt, J = 9.3, 6.5 Hz, 1H), 2.00 (s, 3H), 1.52- 1.61 (m, 2H), 1.34 - 1.45 (m, 2 H), 0.95 (t, J = 7.3 Hz, 3H). LCMS (APCI) m/z: 290.2 [M+H] (100%).

N-{(1S,2R,3R,4R,5S)-2,3-二羥基-1-[(戊氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}乙醯胺(20)N-{(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-[(pentyloxy)methyl]-6,8-dioxabicyclo[3.2.1]oct-4 -yl}acetamide (20)

如上述之一般方法，使用碘戊烷(20當量)，合成化合物(20)。令所欲粗產物經矽膠閃爍層析(乙酸乙酯/甲醇(15：1)洗提)純化以生成呈油之所欲產物(17mg,68%產率)。1 H NMR(400MHz，甲醇-d4 )δ ppm 5.23(d,J=1.5Hz,1H),3.97(dd,J=9.8,1.3Hz,1H),3.94(d,J=9.6Hz,1H),3.88(d,J=4.3Hz,1H),3.79(d,J=8.1Hz,1H),3.73(dd,J=9.8,4.3Hz,1H),3.66(d,J=8.1Hz,1H),3.59(d,J=9.6Hz,1H),3.53(dt,J=9.3,6.5Hz,1H),3.49(dt,J=9.3,6.5Hz,1H),2.01(s,3H),1.53-1.63(m,2H),1.29-1.41(m,4H),0.89-0.97(m,3H)。LCMS(APCI)m/z：304.1[M+H](100%)。The compound (20) was synthesized by the usual method described above using iodopentane (20 equivalents). The desired crude product was purified by EtOAc EtOAc (EtOAc:EtOAc) 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 5.23 (d, J = 1.5 Hz, 1H), 3.97 (dd, J = 9.8, 1.3 Hz, 1H), 3.94 (d, J = 9.6 Hz, 1H) , 3.88 (d, J = 4.3 Hz, 1H), 3.79 (d, J = 8.1 Hz, 1H), 3.73 (dd, J = 9.8, 4.3 Hz, 1H), 3.66 (d, J = 8.1 Hz, 1H) , 3.59 (d, J = 9.6 Hz, 1H), 3.53 (dt, J = 9.3, 6.5 Hz, 1H), 3.49 (dt, J = 9.3, 6.5 Hz, 1H), 2.01 (s, 3H), 1.53 1.63 (m, 2H), 1.29-1.41 (m, 4H), 0.89-0.97 (m, 3H). LCMS (APCI) m/z: 304.1 [M+H] (100%).

N-{(1S,2R,3R,4R,5S)-1-[(己氧基)甲基]-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基}乙醯胺(21)N-{(1S,2R,3R,4R,5S)-1-[(hexyloxy)methyl]-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-4 -yl}acetamide (21)

如上述之一般方法，使用碘己烷(20當量)，合成化合物(21)。令所欲粗產物經矽膠閃爍層析(乙酸乙酯/甲醇(15：1)洗提)純化以生成呈油之產物(56mg)。對產物藉由逆相層析再純化以生成呈固體之所欲產物(7.1mg,15%產率)。1 H NMR(400MHz，甲醇-d4 )δ ppm 5.23(d,J=1.5Hz,1H),3.96(dd,J=10.1,1.3Hz,1H),3.94(d,J=9.6Hz,1H),3.88(d,J=4.3Hz,1H),3.79(d,J=7.8Hz,1H),3.73(dd,J=9.8,4.3Hz,1H),3.66(d,J=8.1Hz,1H),3.59(d,J=9.6Hz,1H),3.53(dt,J=9.3,6.5Hz,1H),3.49(dt,J=9.3,6.5Hz,1H),2.00(s,3H),1.53-1.62(m,2H),1.27-1.50(m,6H),0.89-0.97(m,3H)。LCMS(APCI)m/z：318.1[M+H](100%)。The compound (21) was synthesized by the usual method described above using iodine (20 equivalents). The desired crude product was purified by EtOAc (EtOAc) elute The product was repurified by reverse phase chromatography to give the desired product as a solid (7.1 mg, 15% yield). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 5.23 (d, J = 1.5 Hz, 1H), 3.96 (dd, J = 10.1, 1.3 Hz, 1H), 3.94 (d, J = 9.6 Hz, 1H) , 3.88 (d, J = 4.3 Hz, 1H), 3.79 (d, J = 7.8 Hz, 1H), 3.73 (dd, J = 9.8, 4.3 Hz, 1H), 3.66 (d, J = 8.1 Hz, 1H) , 3.59 (d, J = 9.6 Hz, 1H), 3.53 (dt, J = 9.3, 6.5 Hz, 1H), 3.49 (dt, J = 9.3, 6.5 Hz, 1H), 2.00 (s, 3H), 1.53 1.62 (m, 2H), 1.27-1.50 (m, 6H), 0.89-0.97 (m, 3H). LCMS (APCI) m/z: 318.1 [M+H] (100%).

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(2,5,8,11,14-五氧雜十五烷-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(22)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(2,5,8,11,14-pentaoxapentadecan-1-yl)-6,8 -dioxabicyclo[3.2.1]oct-4-yl]acetamidamine (22)

對化合物(I-e-1)之二氯甲烷(3ml)溶液加入吡啶(0.3ml,4毫莫耳)，令混合物經冷卻至-20℃且加入三氟甲烷磺酸酐(0.047ml,0.28毫莫耳)之二氯甲烷(0.6ml)溶液。 令反應混合物經1小時回溫至-10℃，經二氯甲烷稀釋且連續經1M氫氯酸水溶液、飽和碳酸氫鈉水溶液及鹽水沖洗，置於硫酸鎂上乾燥，經過濾和減壓下濃縮以生成所欲之粗產物，其未經進一步純化而用於下一個步驟。對冷卻至0℃的2,5,8,11-四氧雜十三烷-13-醇(207mg,0.994毫莫耳)之N,N-二甲基甲醯胺溶液加入氫化鈉(39.9mg,1.0毫莫耳)並令反應混合物經攪拌10分鐘。逐滴加入上述粗三氟甲烷磺酸((3aR,4R,7S,8R,8aR)-8-乙醯胺基-2,2-二甲基四氫-4,7-環氧[1,3]二噁呃並[4,5-d]噁呯-4(5H)-基)甲酯之N,N-二甲基甲醯胺溶液(0.5ml)並令反應混合物於0℃下經攪拌25分鐘。令反應經甲醇驟冷並令反應混合物經攪拌5分鐘。令所生成之混合物隨後經減壓下濃縮並令所得之殘餘物溶解於二氯甲烷且經水沖洗。令水層再經二氯甲烷萃取2次。令結合之有機層經水沖洗並經減壓下濃縮。令粗產物經矽膠閃爍層析(乙酸乙酯/甲醇(15：2)洗提)純化以生成所欲產物(85mg,100%產率)。令N-((3aR,4S,7S,8R,8aR)-2,2-二甲基-4-(2,5,8,11,14-五氧雜十五烷基)六氫-4,7-環氧[1,3]二噁呃並[4,5-d]噁呯-8-基)乙醯胺(85mg,0.18毫莫耳)於乙酸/甲醇/水(3.9：1.3：1.3 v/v)混合液中之溶液經隔夜加熱至70℃。令反應混合物於減壓下經濃縮並令所生成之粗產物與甲苯共蒸發2次且經矽膠閃爍層析(10%甲醇/二氯甲烷洗提)純化以生成呈油之所欲產物(22)(15mg)。1 H NMR(400MHz，甲醇-d4 )δ ppm 5.22(d,J=1.3Hz,1H),3.96(d,J=9.6Hz,1H),3.95(dd, J=9.9,1.3Hz,1H),3.89(d,J=4.3Hz,1H),3.78(d,J=8.1Hz,1H),3.59-3.74(m,17H),3.53-3.56(m,2H),3.36(s,3H),1.99(s,3H)。LCMS(APCI)m/z：424.2[M+H](13%),441.3[M+NH4 ](100%)。Pyridine (0.3 ml, 4 mmol) was added to a solution of the compound (Ie-1) in dichloromethane (3 ml). The mixture was cooled to -20 ° C and trifluoromethanesulfonic acid anhydride (0.047 ml, 0.28 m. A solution of dichloromethane (0.6 ml). The reaction mixture was warmed to -10 ° C over 1 h, diluted with dichloromethane and EtOAc EtOAc EtOAc. To give the desired crude product which was used in the next step without further purification. Add sodium hydride (39.9 mg) to a solution of 2,5,8,11-tetraoxatridecane-13-ol (207 mg, 0.994 mmol) cooled to 0 ° C in N,N-dimethylformamide , 1.0 mmol) and the reaction mixture was stirred for 10 minutes. The above crude trifluoromethanesulfonic acid ((3aR, 4R, 7S, 8R, 8aR)-8-acetamido-2,2-dimethyltetrahydro-4,7-epoxy [1,3] was added dropwise. a solution of N,N-dimethylformamide (0.5 ml) of dioxo[4,5-d]oxan-4(5H)-yl)methyl ester and stirring the reaction mixture at 0 °C 25 minutes. The reaction was quenched with methanol and the mixture was stirred for 5 min. The resulting mixture was then concentrated under reduced pressure and the residue obtained was dissolved in dichloromethane and rinsed with water. The aqueous layer was extracted twice more with dichloromethane. The combined organic layers were washed with water and concentrated under reduced pressure. The crude product was purified by EtOAc (EtOAc) elute Let N-((3aR,4S,7S,8R,8aR)-2,2-dimethyl-4-(2,5,8,11,14-pentaoxapentadecyl)hexahydro-4, 7-Epoxy[1,3]dioxamic [4,5-d]oxan-8-yl)acetamide (85 mg, 0.18 mmol) in acetic acid/methanol/water (3.9:1.3:1.3) The solution in the v/v) mixture was heated to 70 ° C overnight. The reaction mixture was concentrated under reduced pressure and the obtained crude material was evaporated twice with toluene and purified by silica gel chromatography (10% methanol / dichloromethane elution) to give the desired product as oil (22 ) (15mg). 1 H NMR (400 MHz, methanol-d 4 ) δ ppm 5.22 (d, J = 1.3 Hz, 1H), 3.96 (d, J = 9.6 Hz, 1H), 3.95 (dd, J = 9.9, 1.3 Hz, 1H) , 3.89 (d, J = 4.3 Hz, 1H), 3.78 (d, J = 8.1 Hz, 1H), 3.59-3.74 (m, 17H), 3.53-3.56 (m, 2H), 3.36 (s, 3H), 1.99 (s, 3H). LCMS (APCI) m / z: 424.2 [M + H] (13%), 441.3 [M + NH 4] (100%).

(1R,2R,3R,4R,5S)-4-乙醯胺基-1-(((4-溴苄醯基)氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二基雙(4-溴苯甲酸酯)(23)(1R, 2R, 3R, 4R, 5S)-4-Ethylamino-1-(((4-bromobenzyl)oxy)methyl)-6,8-dioxabicyclo[3.2.1 Octane-2,3-diylbis(4-bromobenzoate) (23)

對冷卻至室溫的化合物(3)(9mg)之無水N,N-二甲基甲醯胺(500微升)溶液加入N,N-二異丙基乙胺(34微升)和4-(二甲基胺基)吡啶(4.3mg)並隨後加入對溴苄醯氯(44mg)且令所生成之混合物於室溫下經攪拌4.5小時。加入水，令所生成之混合物經乙酸乙酯萃取3次且令結合之有機相連續經0.5M氫氯酸水溶液和鹽水沖洗。令有機相置於硫酸鎂上乾燥，經過濾和濃縮且令粗產物經矽膠閃爍層析(0至100%乙酸乙酯/庚烷梯度洗提)純化以生成產物(23)(23mg,80%產率)。1H NMR(400MHz,CDCl3 )：δ(ppm)7.89-7.95(m,2H),7.78-7.84(m,2H),7.54-7.66(m,6H),7.41-7.46(m,2H),5.87(d,J=8.8Hz,1H),5.80(d, J=4.3Hz,1H),5.60(d,J=1.1Hz,1H),5.44(dd,J=10.2,4.5Hz,1H),4.54-4.64(m,3H),4.15(d,J=8.6Hz,1H),3.93(d,J=8.6Hz,1H),1.95(s,3H)。13 C NMR(101MHz,CDCl3 )δ ppm 170.6,165.6,165.0,164.9,132.1,131.9,131.8,131.4,131.2,131.2,129.3,129.0,128.9,127.7,127.5,127.4,101.8,81.6,69.5,68.8,68.4,62.5,52.7,23.2。藉由蒸汽擴散技術且使用甲醇和庚烷作為溶劑，得到單晶。單晶X射線分析：室溫下使用Bruker APEX繞射儀以進行數據收集。數據收集係由3個Ω掃瞄及低角度和3個高角度所構成；每個經0.5個步驟。此外，收集2個ψ掃瞄以改善吸收正確性品質。結構係非缺面雙晶；藉由忽略第二結構域進行精製。藉由直接方法，於間隔基P2(1)使用SHELX軟體套組(參閱SHELXTL,5.1版，Bruker AXS,1997)以解析結構。隨後藉由全方陣最小平方法精製結構。使用各向異性替代參數，發現並精製所有非氫之原子。位於氮上之氫原子被置於此位置且侷限於合理之位置。殘餘之氫原子被置於經計算之位置且被允許載於彼等之載體原子。最終精製包括所有氫原子之各向同性替代參數。藉由PLATON(參閱文獻A.L.Spek,J.Appl.Cryst.,36,7-13(2003))，使用可能性方法(參閱文獻R.W.W.Hooft et al.,J.Appl.Cryst.,41,96-103(2008))進行絕對結構分析。結果表示該絕對結構已被正確地賦與。該方法計算正確結構之可能性係100.0。經報告之Hooft參數為0.036(估計之標準誤差為0.013)。此外，Flack參 數為0.03(估計之標準誤差為0.04)。最終R指數為5.6%。Fourier最終差異顯示無錯失或誤置之電子密度。切合之結晶、數據收集及精製係示於表1和圖1。To a solution of the compound (3) (9 mg) in anhydrous N,N-dimethylformamide (500 μl) cooled to room temperature was added N,N-diisopropylethylamine (34 μL) and 4- (Dimethylamino)pyridine (4.3 mg) and then p-bromobenzylhydrazine chloride (44 mg) was added and the resulting mixture was stirred at room temperature for 4.5 hours. Water was added, and the resulting mixture was extracted three times with ethyl acetate and the combined organic phases were successively rinsed with 0.5M aqueous hydrochloric acid and brine. The organic phase was dried over MgSO4, EtOAc (EtOAc m. Yield). 1H NMR (400MHz, CDCl 3 ): δ (ppm) 7.89-7.95 (m, 2H), 7.78-7.84 (m, 2H), 7.54-7.66 (m, 6H), 7.41-7.46 (m, 2H), 5.87 (d, J = 8.8 Hz, 1H), 5.80 (d, J = 4.3 Hz, 1H), 5.60 (d, J = 1.1 Hz, 1H), 5.44 (dd, J = 10.2, 4.5 Hz, 1H), 4.54 - 4.64 (m, 3H), 4.15 (d, J = 8.6 Hz, 1H), 3.93 (d, J = 8.6 Hz, 1H), 1.95 (s, 3H). 13 C NMR (101 MHz, CDCl 3 ) δ ppm 170.6, 165.6, 165.0, 164.9, 132.1, 131.9, 131.8, 131.4, 131.2, 131.2, 129.3, 129.0, 128.9, 127.7, 127.5, 127.4, 101.8, 81.6, 69.5, 68.8 , 68.4, 62.5, 52.7, 23.2. A single crystal was obtained by a vapor diffusion technique using methanol and heptane as a solvent. Single crystal X-ray analysis: A Bruker APEX diffractometer was used at room temperature for data collection. The data collection consisted of 3 Ω scans with low angles and 3 high angles; each with 0.5 steps. In addition, two sputum scans were collected to improve the correctness of the absorption. The structure is non-faceted twin; refinement by ignoring the second domain. The SHELX software suite was used on the spacer P2(1) by a direct method (see SHELXTL, version 5.1, Bruker AXS, 1997) to resolve the structure. The structure is then refined by the full square least squares method. All non-hydrogen atoms are found and refined using anisotropic substitution parameters. Hydrogen atoms located on the nitrogen are placed at this location and are limited to a reasonable location. Residual hydrogen atoms are placed in the calculated positions and are allowed to be carried on their carrier atoms. The final refinement includes all isotropic substitution parameters for all hydrogen atoms. The possibility method is used by PLATON (see ALSpek, J. Appl. Cryst., 36, 7-13 (2003)) (see RWWHooft et al., J. Appl. Cryst., 41, 96-103 ( 2008)) Perform an absolute structural analysis. The result indicates that the absolute structure has been correctly assigned. The probability that the method calculates the correct structure is 100.0. The reported Hooft parameter is 0.036 (estimated standard error is 0.013). In addition, the Flack parameter is 0.03 (estimated standard error is 0.04). The final R index was 5.6%. The final difference in Fourier shows the electron density without errors or misplacements. The crystallization, data collection and purification are shown in Table 1 and Figure 1.

(1S,2R,3R,4R,5S)-4-疊氮基-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛烷(l-m-1)(1S, 2R, 3R, 4R, 5S)-4-azido-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[ 3.2.1] Octane (lm-1)

室溫下對(1S,2R,3R,4R,5S)-4-疊氮基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二醇(1)(445mg,2.05毫莫耳)之N,N-二甲基甲醯胺(5ml)溶液加入氫化鈉(60%礦物油分散液，410mg,10.2毫莫耳)。反應物變為極濃稠且不能充分攪拌。加入額外之N,N-二甲基甲醯胺(5ml)並令反應物於室溫下經攪拌30分鐘且隨後逐滴加入苄基溴(1.23ml,10.2毫莫耳)。令反應物於室溫下經隔夜攪拌。次晨，令反應物經水驟冷並經乙酸乙酯萃取3次。令結合之有機層經水和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 40g矽膠管柱；經0至30%乙酸乙酯/庚烷梯度洗提)純化以生成標的化合物(890.0mg,89.1%)。方法C：3分鐘LRMS[M+Na=510]。1 H NMR(甲醇-d4 )δ：7.07-7.52(m,15H),5.31(s,1H),4.81(d,J=5.1Hz,1H),4.78(d,J=5.5Hz,1H),4.68-4.74(m,1H),4.47-4.51(m,1H),4.46(d,J=6.6Hz,1H),4.35-4.42(m,1H),4.12(d,J=3.9Hz,1H),3.87-3.91(m,2H),3.86(d,J=8.2Hz,1H),3.62(d,J=8.2Hz,1H),3.58 (d,J=9.4Hz,1H),3.46(d,J=8.6Hz,1H)。(1S,2R,3R,4R,5S)-4-Azido-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3- at room temperature A solution of the diol (1) (445 mg, 2.05 mmol) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% mineral oil dispersion, 410 mg, 10.2 mmol). The reactants became very thick and could not be stirred sufficiently. Additional N,N-dimethylformamide (5 ml) was added and the mixture was stirred at room temperature for 30 min then benzyl bromide (1.23 ml, 10.2 m The reaction was allowed to stir overnight at room temperature. The next morning, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and filtered and evaporated. The crude product was purified with EtOAc EtOAc EtOAc (EtOAc) Method C: 3 minutes LRMS [M+Na=510]. 1 H NMR (methanol-d 4 ) δ: 7.07-7.52 (m, 15H), 5.31 (s, 1H), 4.81 (d, J = 5.1 Hz, 1H), 4.78 (d, J = 5.5 Hz, 1H) , 4.68-4.74 (m, 1H), 4.47-4.51 (m, 1H), 4.46 (d, J = 6.6 Hz, 1H), 4.35-4.42 (m, 1H), 4.12 (d, J = 3.9 Hz, 1H) ), 3.87-3.91 (m, 2H), 3.86 (d, J = 8.2 Hz, 1H), 3.62 (d, J = 8.2 Hz, 1H), 3.58 (d, J = 9.4 Hz, 1H), 3.46 (d) , J = 8.6 Hz, 1H).

(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-胺(1-n-1)(1S, 2R, 3R, 4R, 5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1] 辛- 4-amine (1-n-1)

令(1S,2R,3R,4R,5S)-4-疊氮基-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛烷(l-m-1)(310mg,0.64毫莫耳)、三苯膦(334mg,1.27毫莫耳)、水(92mg,5.1毫莫耳)及四氫呋喃(10ml)之混合物於65℃下經攪拌16小時。令反應混合物於減壓下經濃縮並令殘餘物載入矽膠管柱。層析(經20%至80%乙酸乙酯之庚烷梯度溶液洗提)生成呈無色膠之標的產物(210mg,72%)。1 H NMR(氯仿-d)δ：7.20-7.37(m,15H),5.29(d,J=1.2Hz,1H),4.90(d,11.5Hz,1H),4.79(d,J=11.5Hz,1H),4.57(d,J=11.7Hz,1H),4.56(d,J=12.1Hz,1H),4.43(d,J=12.1Hz,1H),4.39(d,J=11.7Hz,1H),3.97(d,J=3.9Hz,1H),3.90(d,J=9.0Hz,1H),3.69(d,J=8.2Hz,1H),3.59(d,J=8.2Hz,1H),3.42(d,J=8.6Hz,1H),3.37(dd,J=9.4,3.5Hz,1H),3.07(dd,J=9.4,1.2Hz,1H)；13 C NMR(氯仿-d)δ：131.8,131.6,131.5,128.2,128.2,128.1,128.1,128.0,127.7,127.6,127.6,127.4,103.5,82.6,80.3,74.5,73.3, 73.1,72.2,69.9,69.3,55.1；LCMS(ES+)：1.18分鐘，484.2(M+Na)+ 。(1S,2R,3R,4R,5S)-4-azido-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxbicyclo [3.2.1] a mixture of octane (lm-1) (310 mg, 0.64 mmol), triphenylphosphine (334 mg, 1.27 mmol), water (92 mg, 5.1 mmol) and tetrahydrofuran (10 ml) Stir at 65 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was applied to a silica gel column. Chromatography (extracted with 20% to 80% ethyl acetate in heptane gradient) afforded product (210 mg, 72%). 1 H NMR (chloroform-d) δ: 7.20-7.37 (m, 15H), 5.29 (d, J = 1.2 Hz, 1H), 4.90 (d, 11.5 Hz, 1H), 4.79 (d, J = 11.5 Hz, 1H), 4.57 (d, J = 11.7 Hz, 1H), 4.56 (d, J = 12.1 Hz, 1H), 4.43 (d, J = 12.1 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H) , 3.97 (d, J = 3.9 Hz, 1H), 3.90 (d, J = 9.0 Hz, 1H), 3.69 (d, J = 8.2 Hz, 1H), 3.59 (d, J = 8.2 Hz, 1H), 3.42 (d, J = 8.6 Hz, 1H), 3.37 (dd, J = 9.4, 3.5 Hz, 1H), 3.07 (dd, J = 9.4, 1.2 Hz, 1H); 13 C NMR (chloroform-d) δ: 131.8 , 131.6, 131.5, 128.2, 128.2, 128.1, 128.1, 128.0, 127.7, 127.6, 127.6, 127.4, 103.5, 82.6, 80.3, 74.5, 73.3, 73.1, 72.2, 69.9, 69.3, 55.1; LCMS (ES+): 1.18 minutes , 484.2 (M+Na) + .

N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}乙醯胺(l-n-2)N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1 Octyl-4-yl}acetamide (ln-2)

室溫下對(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-胺(1-n-1)(25mg,0.054毫莫耳)、吡啶(43mg,0.54毫莫耳)及2-甲基-四氫呋喃(1ml)之攪拌混合物一次加入乙酸酐(46mg,0.43毫莫耳)。令反應混合物於室溫下經攪拌16小時並分佈於乙酸乙酯和水中。令有機萃取液經鹽水沖洗，置於無水硫酸鎂上乾燥且經減壓下濃縮。令殘餘物經矽膠管柱(經20%至60%乙酸乙酯之庚烷梯度溶液洗提)純化以生成呈白色固體之標的產物(20mg,73%)。1 H NMR(氯仿-d)δ：7.24-7.43(m,15H),5.35(d,J=1.2Hz,1H),5.06(d,J=8.6Hz,1H),4.96(d,J=11.3Hz,1H),4.74(d,J=12.5Hz,1H),4.58(d,J=11.3Hz,1H),4.42(d,J=12.5Hz,1H),4.40(s,2H),4.30-4.36(m,1H),4.04(d,J=3.9Hz,1H),3.96(d,J=8.6Hz,1H),3.67-3.70(m,1H),3.58-3.61(m,1H),3.41-3.47(m,2H),1.87(s,3H)；13 C NMR(氯仿-d)δ：170.0,138.2, 137.8,137.4,128.7,128.5,128.4,128.3,128.3,128.2,128.1,128.0,127.8,101.6,82.8,75.7,75.0,73.8,73.2,71.5,70.1,69.5,53.5,23.3；LCMS(ES+)：1.87分鐘，526.3(M+Na)+ 。(1S, 2R, 3R, 4R, 5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2. 1] A stirred mixture of oct-4-amine (1-n-1) (25 mg, 0.054 mmol), pyridine (43 mg, 0.54 mmol) and 2-methyl-tetrahydrofuran (1 ml) 46mg, 0.43 millimolar). The reaction mixture was stirred at room temperature for 16 h and distributed over ethyl acetate and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified with a pad of EtOAc (EtOAc:EtOAc) 1 H NMR (chloroform-d) δ: 7.24 - 7.43 (m, 15H), 5.35 (d, J = 1.2 Hz, 1H), 5.06 (d, J = 8.6 Hz, 1H), 4.96 (d, J = 11.3) Hz, 1H), 4.74 (d, J = 12.5 Hz, 1H), 4.58 (d, J = 11.3 Hz, 1H), 4.42 (d, J = 12.5 Hz, 1H), 4.40 (s, 2H), 4.30- 4.36 (m, 1H), 4.04 (d, J = 3.9 Hz, 1H), 3.96 (d, J = 8.6 Hz, 1H), 3.67-3.70 (m, 1H), 3.58-3.61 (m, 1H), 3.41 -3.47 (m, 2H), 1.87 (s, 3H); 13 C NMR (chloroform-d) δ: 170.0, 138.2, 137.8, 137.4, 128.7, 128.5, 128.4, 128.3, 128.3, 128.2, 128.1, 128.0, 127.8 , 101.6,82.8,75.7,75.0,73.8,73.2,71.5,70.1,69.5,53.5,23.3; LCMS (ES +) : 1.87 minutes, 526.3 (M + Na) + .

N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}-2,2,2-三氟乙醯胺(1-n-3)N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1 Octyl-4-yl}-2,2,2-trifluoroacetamide (1-n-3)

室溫下對(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-胺(1-n-1)(75mg,0.16毫莫耳)、吡啶(129mg,1.62毫莫耳)及2-甲基-四氫呋喃(1ml)之攪拌混合物一次加入三氟乙酸酐(102mg,0.49毫莫耳)。令反應混合物於室溫下經攪拌16小時並分佈於乙酸乙酯和水中。令有機萃取液經鹽水沖洗，置於無水硫酸鎂上乾燥且經減壓下濃縮。令殘餘物經矽膠管柱(經10%至40%乙酸乙酯之庚烷梯度溶液洗提)純化以生成呈白色固體之標的產物(60mg,66%)。1 H NMR(氯仿-d)δ：7.25-7.42(m,15H),5.91(d,J=8.6Hz,1H),5.35(d,J=1.2Hz,1H),4.95(d,J=11.3Hz,1H),4.72(d,J=12.5Hz,1H),4.58(d,J=11.3Hz,1H),4.41(s,2H),4.40(d,J=12.5Hz,1H),4.36(t,J=9.8Hz,1H),4.08(d,J=3.9Hz,1H),3.96(d,J=9.0 Hz,1H),3.68-3.72(m,1H),3.60-3.63(m,1H),3.50(dd,J=10.0,3.7Hz,1H),3.45(d,J=8.6Hz,1H)；13 C NMR(氯仿-d)δ：137.9,137.1,136.1,128.9,128.5,128.5,128.4,128.4,128.1,128.1,128.1,127.9,100.6,83.0,75.0,74.9,73.8,72.7,71.4,70.3,69.2,54.1；19 F NMR(氯仿-d)δ：-75.7(s)；LCMS(ES- )：2.11分鐘，556.2(M-H)- 。(1S, 2R, 3R, 4R, 5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxabicyclo[3.2. 1] A stirred mixture of oct-4-amine (1-n-1) (75 mg, 0.16 mmol), pyridine (129 mg, 1.62 mmol) and 2-methyl-tetrahydrofuran (1 ml) Anhydride (102 mg, 0.49 mmol). The reaction mixture was stirred at room temperature for 16 h and distributed over ethyl acetate and water. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified with a pad of EtOAc (EtOAc:EtOAc) 1 H NMR (chloroform-d) δ: 7.25-7.42 (m, 15H), 5.91 (d, J = 8.6 Hz, 1H), 5.35 (d, J = 1.2 Hz, 1H), 4.95 (d, J = 11.3) Hz, 1H), 4.72 (d, J = 12.5 Hz, 1H), 4.58 (d, J = 11.3 Hz, 1H), 4.41 (s, 2H), 4.40 (d, J = 12.5 Hz, 1H), 4.36 ( t, J = 9.8 Hz, 1H), 4.08 (d, J = 3.9 Hz, 1H), 3.96 (d, J = 9.0 Hz, 1H), 3.68-3.72 (m, 1H), 3.60-3.63 (m, 1H) ), 3.50 (dd, J = 10.0, 3.7 Hz, 1H), 3.45 (d, J = 8.6 Hz, 1H); 13 C NMR (chloroform-d) δ: 137.9, 137.1, 136.1, 128.9, 128.5, 128.5, 128.4, 128.4, 128.1, 128.1, 128.1, 127.9, 100.6, 83.0, 75.0, 74.9, 73.8, 72.7, 71.4, 70.3, 69.2, 54.1; 19 F NMR (chloroform-d) δ: -75.7 (s); LCMS ( ES - ): 2.11 minutes, 556.2 (MH) - .

N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}甲磺醯胺(1-n-4)N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1 ]oct-4-yl}methanesulfonamide (1-n-4)

於0℃下對(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-胺(1-n-1)(50mg,0.11毫莫耳)、三乙胺(0.100ml,0.72毫莫耳)及2-甲基-四氫呋喃(1ml)之攪拌混合物逐滴加入甲磺醯氯(0.025ml,0.33毫莫耳)。令反應混合物於室溫下經攪拌16小時並分佈於乙酸乙酯和飽和碳酸氫鈉水溶液中。令有機萃取液經水和鹽水沖洗，置於無水硫酸鎂上乾燥且經減壓下濃縮。令殘餘物經矽膠管柱(經10%至50%乙酸乙酯之庚烷梯度溶液洗提)純化以生成呈白色固體之標的產物(58mg,65%)。1 H NMR(氯仿-d)δ：7.22-7.41(m,15H),5.43(d,J=1.2Hz,1H),4.93(d,J=11.3Hz,1H),4.79(d,J=11.7Hz,1H),4.62 (br.s.,1H),4.56(d,J=11.7Hz,1H),4.54(d,J=11.3Hz,1H),4.41(d,J=12.1Hz,1H),4.37(d,J=12.1Hz,1H),4.05(d,J=3.9Hz,1H),3.92(d,J=8.6Hz,1H),3.74(d,J=8.6Hz,1H),3.68-3.72(m,1H),3.62(d,J=8.6Hz,1H),3.54(dd,J=10.0,3.7Hz,1H),3.44(d,J=9.0Hz,1H),2.90(s,3H)；13 C NMR(氯仿-d)δ：138.0,137.3,137.2,128.7(2),128.5(2),128.4(2),128.3,128.1(2),128.1,127.9(2),127.8(2),102.7,82.9,77.2,77.1,75.0,73.7,73.5,72.8,70.2,69.3,57.7,41.2；LCMS(ES- )：1.97分鐘，538.3(M-H)- 。(1S, 2R, 3R, 4R, 5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxabicyclo[3.2] at 0 °C .1] a stirred mixture of oct-4-amine (1-n-1) (50 mg, 0.11 mmol), triethylamine (0.100 ml, 0.72 mmol) and 2-methyl-tetrahydrofuran (1 ml) Methionine chloride (0.025 ml, 0.33 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 16 hr and then evaporated and evaporated. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified with a pad of EtOAc (EtOAc:EtOAc) 1 H NMR (chloroform-d) δ: 7.22 - 7.41 (m, 15H), 5.43 (d, J = 1.2 Hz, 1H), 4.93 (d, J = 11.3 Hz, 1H), 4.79 (d, J = 11.7) Hz, 1H), 4.62 (br.s., 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.3 Hz, 1H), 4.41 (d, J = 12.1 Hz, 1H) , 4.37 (d, J = 12.1 Hz, 1H), 4.05 (d, J = 3.9 Hz, 1H), 3.92 (d, J = 8.6 Hz, 1H), 3.74 (d, J = 8.6 Hz, 1H), 3.68 -3.72 (m, 1H), 3.62 (d, J = 8.6 Hz, 1H), 3.54 (dd, J = 10.0, 3.7 Hz, 1H), 3.44 (d, J = 9.0 Hz, 1H), 2.90 (s, 3H); 13 C NMR (chloroform-d) δ: 138.0, 137.3, 137.2, 128.7 (2), 128.5 (2), 128.4 (2), 128.3, 128.1 (2), 128.1, 127.9 (2), 127.8 ( 2), 102.7, 82.9, 77.2, 77.1, 75.0, 73.7, 73.5, 72.8, 70.2, 69.3, 57.7, 41.2; LCMS (ES - ): 1.97 min, 538.3 (MH) - .

N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}丙醯胺(1-n-5)N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1 Octyl-4-yl}propanamine (1-n-5)

室溫下對丙酸(23mg,0.31毫莫耳)於四氫呋喃(1ml)中之攪拌混合物一次加入1,1’-羰基二咪唑(33mg,0.20毫莫耳)並令澄清溶液於室溫下經攪拌3小時。室溫下一次加入三乙胺(0.028ml,0.20毫莫耳)和(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-胺(1-n-1)(47mg,0.10毫莫耳)。令反應混合物於室溫下經攪拌16小時並分佈於乙酸乙酯(3ml)、鹽水(2ml)及水 (2ml)中。令有機萃取液經鹽水沖洗，置於無水硫酸鎂上乾燥且經減壓下濃縮。令殘餘物經矽膠管柱(經10%至50%乙酸乙酯之庚烷梯度溶液洗提)純化以生成呈白色固體之標的產物(43mg,82%)。1 H NMR(氯仿-d)δ：7.03-7.58(m,15H),5.35(s,1H),5.09(d,J=8.2Hz,1H),4.95(d,J=11.3Hz,1H),4.72(d,J=12.1Hz,1H),4.57(d,J=11.3Hz,1H),4.43(d,J=12.1Hz,1H),4.39(s,2H),4.31-4.38(m,1H),4.04(d,J=3.9Hz,1H),3.95(d,J=9.0Hz,1H),3.68(d,J=8.2Hz,1H),3.59(d,J=8.2Hz,1H),3.44-3.49(m,1H),3.44(d,J=8.6Hz,1H),2.08(q,J=7.4Hz,2H),1.11(t,J=7.6Hz,3H)；13 C NMR(氯仿-d)δ：173.5,138.1,137.8,137.4,128.6,128.5,128.3,128.3,128.2,128.1,128.0,128.0,127.7,101.6,82.7,75.7,74.9,73.7,73.2,71.5,70.1,69.4,53.3,29.6,9.5；LCMS(ES- )：1.94分鐘，516.4(M-H)- ；LCMS(AP+)：1.94分鐘，518.5(M+H)+ 。Add 1,1'-carbonyldiimidazole (33 mg, 0.20 mmol) to the stirred mixture of propionic acid (23 mg, 0.31 mmol) in tetrahydrofuran (1 ml) at room temperature and let the clear solution pass at room temperature Stir for 3 hours. Add triethylamine (0.028 ml, 0.20 mmol) and (1S, 2R, 3R, 4R, 5S)-2,3-bis(benzyloxy)-1-((benzyloxy) A at room temperature ))-6,8-Dioxabicyclo[3.2.1]oct-4-amine (1-n-1) (47 mg, 0.10 mmol). The reaction mixture was stirred at room temperature for 16 hr then EtOAc (3 mL)EtOAc. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified with a pad of EtOAc (EtOAc:EtOAc) 1 H NMR (chloroform-d) δ: 7.03-7.58 (m, 15H), 5.35 (s, 1H), 5.09 (d, J = 8.2 Hz, 1H), 4.95 (d, J = 11.3 Hz, 1H), 4.72 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 11.3 Hz, 1H), 4.43 (d, J = 12.1 Hz, 1H), 4.39 (s, 2H), 4.31-4.38 (m, 1H) ), 4.04 (d, J = 3.9 Hz, 1H), 3.95 (d, J = 9.0 Hz, 1H), 3.68 (d, J = 8.2 Hz, 1H), 3.59 (d, J = 8.2 Hz, 1H), 3.44-3.49 (m, 1H), 3.44 (d, J = 8.6 Hz, 1H), 2.08 (q, J = 7.4 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H); 13 C NMR (chloroform) -d) δ: 173.5, 138.1, 137.8, 137.4, 128.6, 128.5, 128.3, 128.3, 128.2, 128.1, 128.0, 128.0, 127.7, 101.6, 82.7, 75.7, 74.9, 73.7, 73.2, 71.5, 70.1, 69.4, 53.3 , 29.6,9.5; LCMS (ES -) : 1.94 minutes, 516.4 (MH) -; LCMS (AP +): 1.94 minutes, 518.5 (M + H) + .

N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}-3,3,3-三氟丙醯胺(1-n-6)N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1 Octyl-4-yl}-3,3,3-trifluoropropanamide (1-n-6)

室溫下對3,3,3-三氟丙酸(39mg,0.31毫莫耳)於四氫 呋喃(1ml)中之攪拌混合物一次加入1,1’-羰基二咪唑(33mg,0.20毫莫耳)並令澄清溶液於室溫下經攪拌3小時。室溫下一次加入三乙胺(0.028ml,0.20毫莫耳)和(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-胺(1-n-1)(47mg,0.10毫莫耳)。令反應混合物於室溫下經攪拌16小時並分佈於乙酸乙酯(3ml)、鹽水(2ml)及水(2ml)中。令有機萃取液經鹽水沖洗，置於無水硫酸鎂上乾燥且經減壓下濃縮。令殘餘物經矽膠管柱層析(經10%至50%乙酸乙酯之庚烷梯度溶液洗提)以生成呈白色固體之標的產物(40mg,69%)。1 H NMR(氯仿-d)δ：7.24-7.42(m,15H),5.37(d,J=8.6Hz,1H),5.35(d,J=1.6Hz,1H),4.95(d,J=11.3Hz,1H),4.71(d,J=12.1Hz,1H),4.56(d,J=11.3Hz,1H),4.45(d,J=12.1Hz,1H),4.40(s,2H),4.35-4.40(m,1H),4.05(d,J=3.5Hz,1H),3.95(d,J=8.6Hz,1H),3.71(d,J=8.2Hz,1H),3.61(d,J=8.2Hz,1H),3.50(dd,J=10.0,3.7Hz,1H),3.45(d,J=8.6Hz,1H),2.92(q,J=10.5Hz,2H)；13 C NMR(氯仿-d)δ：162.3,138.0,137.6,137.3,128.7,128.5,128.4,128.3,128.3,128.2,128.0,128.0,127.8,101.1,82.8,75.8,75.0,73.7,73.2,71.9,70.2,69.3,54.0,41.7；19 F NMR(氯仿-d)δ：-62.8(s)；LCMS(ES- )：2.05分鐘，570.3(M-H)- 。Add 1,1'-carbonyldiimidazole (33 mg, 0.20 mmol) to the stirred mixture of 3,3,3-trifluoropropionic acid (39 mg, 0.31 mmol) in tetrahydrofuran (1 ml). The clear solution was allowed to stir at room temperature for 3 hours. Add triethylamine (0.028 ml, 0.20 mmol) and (1S, 2R, 3R, 4R, 5S)-2,3-bis(benzyloxy)-1-((benzyloxy) A at room temperature ))-6,8-Dioxabicyclo[3.2.1]oct-4-amine (1-n-1) (47 mg, 0.10 mmol). The reaction mixture was stirred at room temperature for 16 hr then EtOAc (3 mL)EtOAc. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1 H NMR (chloroform-d) δ: 7.24 - 7.42 (m, 15H), 5.37 (d, J = 8.6 Hz, 1H), 5.35 (d, J = 1.6 Hz, 1H), 4.95 (d, J = 11.3) Hz, 1H), 4.71 (d, J = 12.1 Hz, 1H), 4.56 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.40 (s, 2H), 4.35- 4.40 (m, 1H), 4.05 (d, J = 3.5 Hz, 1H), 3.95 (d, J = 8.6 Hz, 1H), 3.71 (d, J = 8.2 Hz, 1H), 3.61 (d, J = 8.2) Hz, 1H), 3.50 (dd, J = 10.0, 3.7 Hz, 1H), 3.45 (d, J = 8.6 Hz, 1H), 2.92 (q, J = 10.5 Hz, 2H); 13 C NMR (chloroform-d ) δ: 162.3, 138.0, 137.6, 137.3, 128.7, 128.5, 128.4, 128.3, 128.3, 128.2, 128.0, 128.0, 127.8, 101.1, 82.8, 75.8, 75.0, 73.7, 73.2, 71.9, 70.2, 69.3, 54.0, 41.7 ; 19 F NMR (chloroform -d) δ: -62.8 (s) ; LCMS (ES -): 2.05 minutes, 570.3 (MH) -.

N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}-2,2-二氟乙醯胺(1-n-7)N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1 Octyl-4-yl}-2,2-difluoroacetamidamine (1-n-7)

室溫下對二氟乙酸(29mg,0.31毫莫耳)於N,N-二甲基甲醯胺(1ml)中之攪拌混合物一次加入1,1’-羰基二咪唑(33mg,0.20毫莫耳)並令澄清溶液於室溫下經攪拌3小時。室溫下一次加入三乙胺(0.028ml,0.20毫莫耳)和(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-胺(1-n-1)(47mg,0.10毫莫耳)。令反應混合物於室溫下經攪拌16小時並分佈於乙酸乙酯(3ml)、鹽水(2ml)及水(2ml)中。令有機萃取液經鹽水沖洗，置於無水硫酸鎂上乾燥且經濃縮。令殘餘物經矽膠管柱層析(經10%至50%乙酸乙酯之庚烷梯度溶液洗提)以生成呈白色固體之標的產物(32mg,58%)。1 H NMR(氯仿-d)δ：7.14-7.47(m,15H),6.02(d,J=8.6Hz,1H),5.83(t,J=54.2Hz,1H),5.35(s,1H),4.96(d,J=11.3Hz,1H),4.73(d,J=12.5Hz,1H),4.58(d,J=11.3Hz,1H),4.45(d,J=12.1Hz,1H),4.41(s,2H),4.34-4.40(m,1H),4.08(d,J=3.9Hz,1H),3.96(d,J=9.0Hz,1H),3.67-3.75(m,1H),3.59-3.65(m,1H),3.53(dd,J=9.8,3.9Hz,1H),3.46(d,J=8.6Hz,1H)；13 C NMR(氯仿-d)δ：162.6,138.0,137.3,128.8,128.5,128.4,128.3,128.1,128.0,127.8,108.3(t,J=253.1Hz),100.9,82.9,75.3,75.0,73.8,72.9,71.6, 70.2,69.3,53.5；19 F NMR(氯仿-d)δ：-126.1(d,J=53.1Hz)；LCMS(ES- )：2.05分鐘，538.2(M-H)- 。Add 1,1'-carbonyldiimidazole (33 mg, 0.20 mmol) to a stirred mixture of difluoroacetic acid (29 mg, 0.31 mmol) in N,N-dimethylformamide (1 ml) at room temperature. And the clear solution was stirred at room temperature for 3 hours. Add triethylamine (0.028 ml, 0.20 mmol) and (1S, 2R, 3R, 4R, 5S)-2,3-bis(benzyloxy)-1-((benzyloxy) A at room temperature ))-6,8-Dioxabicyclo[3.2.1]oct-4-amine (1-n-1) (47 mg, 0.10 mmol). The reaction mixture was stirred at room temperature for 16 hr then EtOAc (3 mL)EtOAc. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 1 H NMR (chloroform-d) δ: 7.14 - 7.47 (m, 15H), 6.02 (d, J = 8.6 Hz, 1H), 5.83 (t, J = 54.2 Hz, 1H), 5.35 (s, 1H), 4.96 (d, J = 11.3 Hz, 1H), 4.73 (d, J = 12.5 Hz, 1H), 4.58 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 12.1 Hz, 1H), 4.41 ( s, 2H), 4.34-4.40 (m, 1H), 4.08 (d, J = 3.9 Hz, 1H), 3.96 (d, J = 9.0 Hz, 1H), 3.67-3.75 (m, 1H), 3.59-3.65 (m, 1H), 3.53 (dd, J = 9.8, 3.9 Hz, 1H), 3.46 (d, J = 8.6 Hz, 1H); 13 C NMR (chloroform-d) δ: 162.6, 138.0, 137.3, 128.8, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8, 108.3 (t, J = 253.1 Hz), 100.9, 82.9, 75.3, 75.0, 73.8, 72.9, 71.6, 70.2, 69.3, 53.5; 19 F NMR (chloroform-d) δ: -126.1 (d, J = 53.1 Hz); LCMS (ES - ): 2.05 min, 538.2 (MH) - .

{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}胺甲酸三級丁酯(1-n-8){(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1] octane -4-yl}-tert-butyl amide (1-n-8)

室溫下對(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-胺(1-n-1)(120mg,0.26毫莫耳)、N,N-二甲基胺基吡啶(DMAP)(6.4mg,0.052毫莫耳)及四氫呋喃(2ml)之攪拌混合物一次加入二碳酸二(三級丁酯)(113mg,0.52毫莫耳)。令反應混合物於室溫下經攪拌16小時並經減壓下濃縮。令殘餘物經矽膠管柱(經10%至40%乙酸乙酯之庚烷梯度溶液洗提)純化以生成呈白色固體之標的產物(104mg,71%)。1 H NMR(氯仿-d)δ：7.17-7.45(m,15H),5.35(s,1H),4.97(d,J=11.3Hz,1H),4.74(d,J=12.1Hz,1H),4.57(d,J=11.3Hz,2H),4.47(d,J=7.0Hz,1H),4.39(s,2H),4.09(br.s.,1H),4.01(d,J=3.9Hz,1H),3.93(d,J=9.0Hz,1H),3.63-3.71(m,1H),3.54-3.62(m,1H),3.38-3.48(m,2H),1.47(s,9H)；13 C NMR(氯仿-d)δ：155.2,138.2,137.8,137.4,128.5,128.4,128.3,128.3,128.0,127.9,127.8,127.7,102.2,82.8,79.4, 74.8,73.7,73.4,72.0,70.0,69.4,54.6,31.9,28.4；LCMS(AP+)：2.25分鐘，462.2(M-Boc+H)+ 。(1S, 2R, 3R, 4R, 5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxabicyclo[3.2. 1] oct-4-amine (1-n-1) (120 mg, 0.26 mmol), N,N-dimethylaminopyridine (DMAP) (6.4 mg, 0.052 mmol) and tetrahydrofuran (2 ml) The stirred mixture was added in one portion to di(tertiary butyl dicarbonate) (113 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 16 hr and then concentrated. The residue was purified with a pad of EtOAc (EtOAc:EtOAc) 1 H NMR (chloroform-d) δ: 7.17-7.45 (m, 15H), 5.35 (s, 1H), 4.97 (d, J = 11.3 Hz, 1H), 4.74 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 11.3 Hz, 2H), 4.47 (d, J = 7.0 Hz, 1H), 4.39 (s, 2H), 4.09 (br.s., 1H), 4.01 (d, J = 3.9 Hz, 1H), 3.93 (d, J = 9.0Hz, 1H), 3.63-3.71 (m, 1H), 3.54-3.62 (m, 1H), 3.38-3.48 (m, 2H), 1.47 (s, 9H); 13 C NMR (chloroform-d) δ: 155.2, 138.2, 137.8, 137.4, 128.5, 128.4, 128.3, 128.3, 128.0, 127.9, 127.8, 127.7, 102.2, 82.8, 79.4, 74.8, 73.7, 73.4, 72.0, 70.0, 69.4 , 54.6, 31.9, 28.4; LCMS (AP+): 2.25 min, 462.2 (M-Boc+H) + .

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]丙醯胺(25)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]-propyl Guanamine (25)

令N-((1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)丙醯胺(1-n-5)(42mg,0.081毫莫耳)、1-甲基-1,4-環己二烯(0.093ml,0.81毫莫耳)、10% Pd/C(20mg)及2-丙醇(2.5ml)之混合物於80℃下經攪拌3小時。加入水(0.2ml)並令全體混合物載入矽膠且於旋轉蒸發器上乾燥。令產物經矽膠管柱(經4%至15%甲醇之二氯甲烷梯度溶液洗提)純化以生成呈無色膠之標的化合物(12mg,60%)。1 H NMR(甲醇-d4 )δ：5.21(d,J=1.6Hz,1H),3.95(dd,J=10.1,1.2Hz,1H),3.92(d,J=11.3Hz,1H),3.87(d,J=3.9Hz,1H),3.81(d,J=11.3Hz,1H),3.75(d,J=8.2Hz,1H),3.71-3.76(m,2H),3.68(d,J=8.2Hz,1H),3.35(s,1H),2.26(q,J=7.4Hz,2H),1.13(t,J=7.4Hz,3H)；13 C NMR(甲醇-d4 )δ：177.7,102.6,84.9,70.4,69.1,69.0,61.9,56.0,30.0,10.3；LCMS(AP+)：0.25分鐘，248.2(M+H)+ 。Let N-((1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxabicyclo[3.2. 1]oct-4-yl)propanamide (1-n-5) (42 mg, 0.081 mmol), 1-methyl-1,4-cyclohexadiene (0.093 ml, 0.81 mmol), A mixture of 10% Pd/C (20 mg) and 2-propanol (2.5 ml) was stirred at 80 ° C for 3 hours. Water (0.2 ml) was added and the whole mixture was loaded onto a silicone and dried on a rotary evaporator. The product was purified on a silica gel column eluting with a gradient of 4% to 15% methanol in dichloromethane to yield the title compound (12 mg, 60%). 1 H NMR (methanol-d 4 ) δ: 5.21 (d, J = 1.6 Hz, 1H), 3.95 (dd, J = 10.1, 1.2 Hz, 1H), 3.92 (d, J = 11.3 Hz, 1H), 3.87 (d, J = 3.9 Hz, 1H), 3.81 (d, J = 11.3 Hz, 1H), 3.75 (d, J = 8.2 Hz, 1H), 3.71-3.76 (m, 2H), 3.68 (d, J = 8.2 Hz, 1H), 3.35 (s, 1H), 2.26 (q, J = 7.4 Hz, 2H), 1.13 (t, J = 7.4 Hz, 3H); 13 C NMR (methanol-d 4 ) δ: 177.7, 102.6, 84.9, 70.4, 69.1, 69.0, 61.9, 56.0, 30.0, 10.3; LCMS (AP+): 0.25 min, 248.2 (M+H) + .

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜 雙環[3.2.1]辛-4-基]-2,2,2-三氟乙醯胺(24)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxa Bicyclo[3.2.1]oct-4-yl]-2,2,2-trifluoroacetamide (24)

令N-((1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)-2,2,2-三氟乙醯胺(1-n-3)(20mg,0.036毫莫耳)、1-甲基-1,4-環己二烯(0.093ml,0.81毫莫耳)、10% Pd/C(20mg)及2-丙醇(2.5ml)之混合物於80℃下經攪拌3小時。加入水(0.2ml)並令全體混合物載入矽膠且於旋轉蒸發器上乾燥。令產物經矽膠管柱(經4%至15%甲醇之二氯甲烷梯度溶液洗提)純化以生成呈無色膠之標的化合物(7.2mg,69%)。1 H NMR(甲醇-d4 )δ：5.25(d,J=1.2Hz,1H),4.02(d,J=8.6Hz,1H),3.90(d,J=7.0Hz,1H),3.88-3.95(m,2H),3.82(d,J=11.7Hz,1H),3.78(d,J=7.8Hz,1H),3.71(d,J=7.8Hz,1H),3.35(s,1H)；13 C NMR(甲醇-d4 )δ：159.8,102.3,85.5,70.8,69.7,68.4,62.2,57.4；19 F NMR(氯仿-d)δ：-77.0(s)；LCMS(AP+)：0.42分鐘，288.2(M+H)+ 。Let N-((1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxabicyclo[3.2. 1] oct-4-yl)-2,2,2-trifluoroacetamide (1-n-3) (20 mg, 0.036 mmol), 1-methyl-1,4-cyclohexadiene ( A mixture of 0.093 ml, 0.81 mmol, 10% Pd/C (20 mg) and 2-propanol (2.5 ml) was stirred at 80 ° C for 3 hours. Water (0.2 ml) was added and the whole mixture was loaded onto a silicone and dried on a rotary evaporator. The product was purified on a silica gel column eluting with 4% to 15% methanol in dichloromethane gradient eluting to afford compound (7.2 mg, 69%). 1 H NMR (methanol-d 4 ) δ: 5.25 (d, J = 1.2 Hz, 1H), 4.02 (d, J = 8.6 Hz, 1H), 3.90 (d, J = 7.0 Hz, 1H), 3.88 - 3.95 (m, 2H), 3.82 ( d, J = 11.7Hz, 1H), 3.78 (d, J = 7.8Hz, 1H), 3.71 (d, J = 7.8Hz, 1H), 3.35 (s, 1H); 13 C NMR (methanol-d 4 ) δ: 159.8, 102.3, 85.5, 70.8, 69.7, 68.4, 62.2, 57.4; 19 F NMR (chloroform-d) δ: -77.0 (s); LCMS (AP+): 0.42 min, 288.2 (M+H) + .

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]甲磺醯胺(26)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]- Sulfonamide (26)

令N-((1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基) 甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)甲磺醯胺(1-n-4)(19mg,0.035毫莫耳)、1-甲基-1,4-環己二烯(0.093ml,0.81毫莫耳)、10% Pd/C(20mg)及2-丙醇(2.5ml)之混合物於80℃下經攪拌3小時。加入水(0.2ml)並令全體混合物載入矽膠且於旋轉蒸發器上乾燥。令產物經矽膠管柱(經4%至15%甲醇之二氯甲烷梯度溶液洗提)純化以生成呈無色膠之標的化合物(6.4mg,68%)。1 H NMR(甲醇-d4 )δ：5.26(d,J=1.6Hz,1H),3.91(d,J=11.3Hz,1H),3.87(d,J=4.3Hz,1H),3.80(d,J=11.3Hz,1H),3.73(d,J=7.8Hz,1H),3.68(d,J=7.8Hz,1H),3.66-3.71(m,1H),3.37(dd,J=9.8,1.6Hz,1H),3.35(s,1H),3.04(s,3H)；13 C NMR(甲醇-d4 )δ：104.6,85.1,70.9,69.8,69.3,62.0,60.2,41.7；LCMS(ES- )：0.15分鐘，268.0(M-H)- 。Let N-((1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxabicyclo[3.2. 1]oct-4-yl)methanesulfonamide (1-n-4) (19 mg, 0.035 mmol), 1-methyl-1,4-cyclohexadiene (0.093 ml, 0.81 mmol) A mixture of 10% Pd/C (20 mg) and 2-propanol (2.5 ml) was stirred at 80 ° C for 3 hours. Water (0.2 ml) was added and the whole mixture was loaded onto a silicone and dried on a rotary evaporator. The product was purified on a silica gel column eluting with 4% to 15% methanol in dichloromethane gradient eluting to afford compound (6.4 mg, 68%). 1 H NMR (methanol-d 4 ) δ: 5.26 (d, J = 1.6 Hz, 1H), 3.91 (d, J = 11.3 Hz, 1H), 3.87 (d, J = 4.3 Hz, 1H), 3.80 (d) , J = 11.3 Hz, 1H), 3.73 (d, J = 7.8 Hz, 1H), 3.68 (d, J = 7.8 Hz, 1H), 3.66 - 3.71 (m, 1H), 3.37 (dd, J = 9.8, 1.6 Hz, 1H), 3.35 (s, 1H), 3.04 (s, 3H); 13 C NMR (methanol-d 4 ) δ: 104.6, 85.1, 70.9, 69.8, 69.3, 62.0, 60.2, 41.7; LCMS (ES) - ): 0.15 minutes, 268.0 (MH) - .

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-2,2-二氟乙醯胺(27)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]- 2,2-difluoroacetamide (27)

對微波小管(5ml)中N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}-2,2-二氟乙醯胺(1-n-7)(32.0mg,0.059毫莫耳)之2-丙醇(1.0ml)和四氫呋喃(0.5ml)溶液先後加入1-甲基-1,4-環己二烯(0.2ml,2毫莫耳)和10% Pd/C(50%濕重wt/wt,20.0mg,0毫莫耳)。該小管經密封並經加熱至80℃達4小 時。經4小時後，TLC(10%甲醇/二氯甲烷)顯示反應未完全但生成所欲之產物。加入額外之1-甲基-1,4-環己二烯(0.2ml,2毫莫耳)並令反應物再經密封且經隔夜(18小時)加熱至80℃。經全部22小時後，令反應物經甲醇稀釋並經通過Life Sciences Acrodisc 25mm注射濾器過濾。令濾液經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈固體之標的化合物(5.0mg,31%)。方法C：3分鐘LRMS[M+Na=292]。1 H NMR(甲醇-d4 )δ：6.06(t,J=54.2Hz,1H),5.25(s,1H),4.02(d,J=9.4Hz,1H),3.92(d,J=11.7Hz,1H),3.84-3.90(m,2H),3.81(d,J=11.7Hz,1H),3.78(d,J=8.2Hz,1H),3.70(d,J=8.2Hz,1H)。N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-di in microwave tubules (5ml) Oxybicyclo[3.2.1]oct-4-yl}-2,2-difluoroacetamide (1-n-7) (32.0 mg, 0.059 mmol) of 2-propanol (1.0 ml) and Tetrahydrofuran (0.5 ml) was added with 1-methyl-1,4-cyclohexadiene (0.2 ml, 2 mmol) and 10% Pd/C (50% wet weight wt/wt, 20.0 mg, 0 mM). Moore). The tube was sealed and heated to 80 °C for 4 hours. After 4 hours, TLC (10% methanol / dichloromethane) showed that the reaction was not complete but the desired product was formed. Additional 1-methyl-1,4-cyclohexadiene (0.2 ml, 2 mmol) was added and the reaction was resealed and heated to 80 ° C overnight (18 h). After all 22 hours, the reaction was diluted with MeOH and filtered thru a &lt The filtrate was concentrated under reduced pressure. The crude product was purified with EtOAc (EtOAc) elute Method C: 3 minutes LRMS [M+Na=292]. 1 H NMR (methanol-d 4 ) δ: 6.06 (t, J = 54.2 Hz, 1H), 5.25 (s, 1H), 4.02 (d, J = 9.4 Hz, 1H), 3.92 (d, J = 11.7 Hz) , 1H), 3.84-3.90 (m, 2H), 3.81 (d, J = 11.7 Hz, 1H), 3.78 (d, J = 8.2 Hz, 1H), 3.70 (d, J = 8.2 Hz, 1H).

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-3,3,3-三氟丙醯胺(28)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]- 3,3,3-trifluoropropanamide (28)

對微波小管(5ml)中N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}-3,3,3-三氟丙醯胺(1-n-6)(40.0mg,0.070毫莫耳)之2-丙醇(1.0ml)和四氫呋喃(0.5ml)溶液先後加入1-甲基-1,4-環己二烯(0.2ml,1.75毫莫耳)和10% Pd/C(50%濕重wt/wt,20.0mg,0毫莫耳)。該小管經密封並經加熱至80℃達4小時。經4小時後，令反應物經甲醇稀釋並經通過Life Sciences Acrodisc 25mm注射濾器過濾。令濾液經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈固體之標的化合物(15.3mg,73%)。LRMS[M+1=302]。1 H NMR(甲醇-d4 )δ：5.23(s,1H),3.99(d,J=9.8Hz,1H),3.92(d,J=11.3Hz,1H),3.87(d,J=4.3Hz,1H),3.81(d,J=11.3Hz,1H),3.76(d,J=8.2Hz,1H),3.71-3.74(m,1H),3.69(d,J=8.2Hz,1H),3.22(qd,J=10.7,2.5Hz,2H)。N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-di in microwave tubules (5ml) Oxybicyclo[3.2.1]oct-4-yl}-3,3,3-trifluoropropionamide (1-n-6) (40.0 mg, 0.070 mmol) 2-propanol (1.0 ml) And tetrahydrofuran (0.5 ml) solution was added 1-methyl-1,4-cyclohexadiene (0.2 ml, 1.75 mmol) and 10% Pd/C (50% wet weight wt/wt, 20.0 mg, respectively). 0 millimoles). The tube was sealed and heated to 80 °C for 4 hours. After 4 hours, the reaction was diluted with methanol and filtered thru a &lt The filtrate was concentrated under reduced pressure. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc. LRMS [M+1=302]. 1 H NMR (methanol-d 4 ) δ: 5.23 (s, 1H), 3.99 (d, J = 9.8 Hz, 1H), 3.92 (d, J = 11.3 Hz, 1H), 3.87 (d, J = 4.3 Hz) , 1H), 3.81 (d, J = 11.3 Hz, 1H), 3.76 (d, J = 8.2 Hz, 1H), 3.71-3.74 (m, 1H), 3.69 (d, J = 8.2 Hz, 1H), 3.22 (qd, J = 10.7, 2.5 Hz, 2H).

N-{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}-N-甲基乙醯胺(l-o-1)N-{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1 Octyl-4-yl}-N-methylacetamide (lo-1)

室溫下對N-((1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)乙醯胺(l-n-2)(19mg,0.038毫莫耳)和N,N-二甲基甲醯胺(1.5ml)之攪拌混合物一次加入氫化鈉(60%礦物油懸浮液)並令混合物經攪拌30分鐘。室溫下一次加入碘甲烷(16mg,0.11毫莫耳)。令反應混合物於室溫下經攪拌16小時並分佈於乙酸乙酯(3ml)、鹽水(2ml)及水(2ml)中。令有機萃取液經鹽水沖洗，置於無水硫酸鎂上乾燥且經減壓下濃縮。令殘餘物經矽膠管柱(經10%至50%乙酸乙酯之庚烷梯度溶液洗 提)純化以生成呈無色膠之標的產物(19mg,97%)。旋轉異構體之混合物(3：1)。旋轉異構體1：1 H NMR(氯仿-d)d：7.21-7.43(m,15H),5.37(s,1H),4.93(d,J=10.9Hz,1H),4.65(d,J=11.7Hz,1H),4.54(d,J=11.3Hz,1H),4.50(d,J=11.7Hz,1H),4.37-4.45(m,2H),4.15(d,J=9.8Hz,1H),4.09(d,J=3.5Hz,1H),3.93(d,J=8.6Hz,1H),3.85(dd,J=10.1,3.5Hz,1H),3.78(d,J=8.2Hz,1H),3.64(d,J=8.2Hz,1H),3.45(d,J=8.6Hz,1H),2.80(s,3H),2.19(s,3H)；旋轉異構體2：1 H NMR(氯仿-d)d：7.21-7.43(m,15H),5.27(s,1H),5.12(d,J=10.9Hz,1H),4.94-4.98(m,1H),4.74(d,J=12.1Hz,1H),4.56(d,J=11.7Hz,1H),4.46(d,J=11.3Hz,1H),4.37-4.46(m,2H),4.14-4.17(m,1H),3.97(d,J=8.6Hz,1H),3.82-3.89(m,2H),3.79(d,J=8.2Hz,1H),3.60-3.63(m,1H),2.71(s,3H),2.08(s,3H)；13 C NMR(氯仿-d)d：172.2,138.0,137.3,137.2,128.6,128.5,128.5,128.4,128.1,128.0,127.9,127.9,127.9,127.8,103.2,83.2,75.2,74.1,73.8,73.7,73.0,72.4,70.1,69.2,61.2,28.0,22.2；LCMS(AP+)：1.99分鐘，518.0(M+H)+ 。N-((1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxbicyclo ring at room temperature a stirred mixture of [3.2.1] oct-4-yl)acetamide (ln-2) (19 mg, 0.038 mmol) and N,N-dimethylformamide (1.5 ml). 60% mineral oil suspension) and the mixture was stirred for 30 minutes. Methyl iodide (16 mg, 0.11 mmol) was added in one portion at room temperature. The reaction mixture was stirred at room temperature for 16 hr then EtOAc (3 mL)EtOAc. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified with a pad of EtOAc (EtOAc:EtOAc) A mixture of rotamers (3:1). Rotamer 1: 1 H NMR (chloroform-d) d: 7.21 - 7.43 (m, 15H), 5.37 (s, 1H), 4.93 (d, J = 10.9 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.54 (d, J = 11.3 Hz, 1H), 4.50 (d, J = 11.7 Hz, 1H), 4.37 - 4.45 (m, 2H), 4.15 (d, J = 9.8 Hz, 1H) , 4.09 (d, J = 3.5 Hz, 1H), 3.93 (d, J = 8.6 Hz, 1H), 3.85 (dd, J = 10.1, 3.5 Hz, 1H), 3.78 (d, J = 8.2 Hz, 1H) , 3.64 (d, J = 8.2 Hz, 1H), 3.45 (d, J = 8.6 Hz, 1H), 2.80 (s, 3H), 2.19 (s, 3H); rotamer 2: 1 H NMR (chloroform) -d)d: 7.21 - 7.43 (m, 15H), 5.27 (s, 1H), 5.12 (d, J = 10.9 Hz, 1H), 4.94 - 4.98 (m, 1H), 4.74 (d, J = 12.1 Hz) , 1H), 4.56 (d, J = 11.7 Hz, 1H), 4.46 (d, J = 11.3 Hz, 1H), 4.37 - 4.46 (m, 2H), 4.14 - 4.17 (m, 1H), 3.97 (d, J=8.6 Hz, 1H), 3.82-3.89 (m, 2H), 3.79 (d, J = 8.2 Hz, 1H), 3.60-3.63 (m, 1H), 2.71 (s, 3H), 2.08 (s, 3H) 13 C NMR (chloroform-d) d: 172.2, 138.0, 137.3, 137.2, 128.6, 128.5, 128.5, 128.4, 128.1, 128.0, 127.9, 127.9, 127.9, 127.8, 103.2, 83.2, 75.2, 74.1, 73.8, 73.7, 73.0, 72.4, 70.1, 69.2, 61.2, 28.0, 22.2; LCMS (AP+): 1.99 min, 518.0 (M+H) + .

N-{(1S,2R,3R,4R,5S)-2,3-雙(芾氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}-N-甲基甲磺醯胺(l-o-2)N-{(1S,2R,3R,4R,5S)-2,3-bis(decyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1 Octyl-4-yl}-N-methylmethanesulfonamide (lo-2)

室溫下對N-((1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)甲磺醯胺(1-n-4)(19mg,0.035毫莫耳)和N,N-二甲基甲醯胺(1.5ml)之攪拌混合物一次加入氫化鈉(60%礦物油懸浮液)並令混合物經攪拌30分鐘。室溫下一次加入碘甲烷(16mg,0.11毫莫耳)。令反應混合物於室溫下經攪拌16小時並分佈於乙酸乙酯(3ml)、鹽水(2ml)及水(2ml)中。令有機萃取液經鹽水沖洗，置於無水硫酸鎂上乾燥且經減壓下濃縮。令殘餘物經矽膠管柱(經10%至50%乙酸乙酯之庚烷梯度溶液洗提)純化以生成呈無色膠之標的產物(11mg,56%)。1 H NMR(氯仿-d)δ：7.25-7.39(m,15H),5.39(d,J=0.8Hz,1H),4.93(d,J=11.7Hz,1H),4.80(d,J=11.3Hz,1H),4.58(d,J=11.3Hz,1H),4.45(d,J=11.7Hz,1H),4.43(d,J=11.7Hz,1H),4.41(d,J=11.7Hz,1H),4.21(d,J=3.5Hz,1H),4.18(d,J=10.5Hz,1H),3.98(d,J=8.6Hz,1H),3.87(dd,J=10.5,3.9Hz,1H),3.82(d,J=8.6Hz,1H),3.62(d,J=8.2Hz,1H),3.45(d,J=9.0Hz,1H),2.83(s,3H),2.68(s,3H)；13 C NMR(氯仿-d)δ：138.1,137.3,136.8,128.7,128.5,128.4,128.4,128.1,128.1,128.0,127.8,104.6,82.9,74.9,73.8,73.5,73.3,71.6,70.3,69.4,59.7,37.5, 29.5；LCMS(AP+)：2.08分鐘，575.8(M+Na)+ 。N-((1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxbicyclo ring at room temperature [3.2.1] oct-4-yl) a mixture of methanesulfonamide (1-n-4) (19 mg, 0.035 mmol) and N,N-dimethylformamide (1.5 ml) was added in one portion. Sodium hydride (60% mineral oil suspension) and the mixture was stirred for 30 minutes. Methyl iodide (16 mg, 0.11 mmol) was added in one portion at room temperature. The reaction mixture was stirred at room temperature for 16 hr then EtOAc (3 mL)EtOAc. The organic extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified with a pad of EtOAc (EtOAc:EtOAc) 1 H NMR (chloroform -d) δ: 7.25-7.39 (m, 15H), 5.39 (d, J = 0.8Hz, 1H), 4.93 (d, J = 11.7Hz, 1H), 4.80 (d, J = 11.3 Hz, 1H), 4.58 (d, J = 11.3 Hz, 1H), 4.45 (d, J = 11.7 Hz, 1H), 4.43 (d, J = 11.7 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 4.21 (d, J = 3.5 Hz, 1H), 4.18 (d, J = 10.5 Hz, 1H), 3.98 (d, J = 8.6 Hz, 1H), 3.87 (dd, J = 10.5, 3.9 Hz, 1H), 3.82 (d, J = 8.6 Hz, 1H), 3.62 (d, J = 8.2 Hz, 1H), 3.45 (d, J = 9.0 Hz, 1H), 2.83 (s, 3H), 2.68 (s, 3H); 13 C NMR (chloroform-d) δ: 138.1, 137.3, 136.8, 128.7, 128.5, 128.4, 128.4, 128.1, 128.1, 128.0, 127.8, 104.6, 82.9, 74.9, 73.8, 73.5, 73.3, 71.6, 70.3 , 69.4,59.7,37.5, 29.5; LCMS (AP +): 2.08 minutes, 575.8 (M + Na) + .

{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}甲基胺甲酸三級丁酯(l-o-3){(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2.1] octane -4-yl}methylaminocarbamic acid tert-butyl butyl ester (lo-3)

室溫下對{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}胺甲酸三級丁酯(l-n-8)(100mg,0.178毫莫耳)之N,N-二甲基甲醯胺(1.5ml)攪拌溶液加入氫化鈉(60%礦物油分散液，8.55mg,0.214毫莫耳)。令反應物經攪拌1小時並隨後加入碘甲烷(0.055ml,0.89毫莫耳)。令反應物於室溫下經隔夜攪拌。經24小時後，令反應物經水驟冷並經乙酸乙酯萃取3次。令結合之有機層經水和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 12g矽膠管柱；經0至100%乙酸乙酯/二氯甲烷梯度洗提)純化以生成標的化合物(78mg,63%)。方法C：3分鐘LRMS[M+Na=598]。1 H NMR(化合物係2種旋轉異構體(約1：1)之混合物)。{(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-dioxabicyclo[3.2] at room temperature .1] octyl-4-ylamine carboxylic acid tert-butyl ester (ln-8) (100 mg, 0.178 mmol) of N,N-dimethylformamide (1.5 ml) was added to a stirred solution of sodium hydride (60). % mineral oil dispersion, 8.55 mg, 0.214 mmol. The reaction was allowed to stir for 1 hour and then iodomethane (0.055 mL, 0.89 mmol). The reaction was allowed to stir overnight at room temperature. After 24 hours, the reaction was quenched with water and extracted with EtOAc EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate and filtered and evaporated. The crude product was purified with EtOAc EtOAc (EtOAc) eluting Method C: 3 minutes LRMS [M+Na=598]. 1 H NMR (compound is a mixture of 2 rotamers (about 1:1)).

旋轉異構體1：1 H NMR(甲醇-d4 )δ：7.08-7.48(m,15H),5.26(s,1H),4.83-4.90(m,1H),4.73(d,J=11.7Hz, 1H),4.47-4.58(m,3H),4.36-4.47(m,2H),4.21(d,J=3.5Hz,1H),3.98(dd,J=10.7,3.3Hz,1H),3.92(d,J=8.2Hz,2H),3.61(d,J=7.8Hz,1H),3.47(dd,J=8.6,3.9Hz,1H),2.75(s,3H),1.42(s,9H)。Rotamer 1: 1 H NMR (methanol-d 4 ) δ: 7.08-7.48 (m, 15H), 5.26 (s, 1H), 4.83-4.90 (m, 1H), 4.73 (d, J = 11.7 Hz) , 1H), 4.47-4.58 (m, 3H), 4.36-4.47 (m, 2H), 4.21 (d, J = 3.5 Hz, 1H), 3.98 (dd, J = 10.7, 3.3 Hz, 1H), 3.92 ( d, J = 8.2 Hz, 2H), 3.61 (d, J = 7.8 Hz, 1H), 3.47 (dd, J = 8.6, 3.9 Hz, 1H), 2.75 (s, 3H), 1.42 (s, 9H).

旋轉異構體2：1 H NMR(甲醇-d4 )δ：7.08-7.48(m,15H),5.21(s,1H),4.83-4.90(m,1H),4.73(d,J=11.7Hz,1H),4.47-4.58(m,3H),4.36-4.47(m,2H),4.21(d,J=3.5Hz,1H),3.98(dd,J=10.7,3.3Hz,1H),3.92(d,J=8.2Hz,2H),3.61(d,J=7.8Hz,1H),3.47(dd,J=8.6,3.9Hz,1H),2.70(s,3H),1.44-1.52(m,9H)。Rotamer 2: 1 H NMR (methanol-d 4 ) δ: 7.08-7.48 (m, 15H), 5.21 (s, 1H), 4.83-4.90 (m, 1H), 4.73 (d, J = 11.7 Hz) , 1H), 4.47-4.58 (m, 3H), 4.36-4.47 (m, 2H), 4.21 (d, J = 3.5 Hz, 1H), 3.98 (dd, J = 10.7, 3.3 Hz, 1H), 3.92 ( d, J = 8.2 Hz, 2H), 3.61 (d, J = 7.8 Hz, 1H), 3.47 (dd, J = 8.6, 3.9 Hz, 1H), 2.70 (s, 3H), 1.44-1.52 (m, 9H) ).

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-N-甲基乙醯胺(29)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]- N-methylacetamide (29)

令N-((1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)-N-甲基乙醯胺(l-o-1)(19mg,0.037毫莫耳)、1-甲基-1,4-環己二烯(0.093ml,0.81毫莫耳)、10% Pd/C(20mg)及2-丙醇(2.5ml)之混合物於80℃下經攪拌3小時。加入水(0.2ml)並令全體混合物載入矽膠且於旋轉蒸發器上乾燥。令產物經矽膠管柱(經4%至15%甲醇/二氯甲烷梯度洗提)純化以生成呈無色膠之標的化合物(4.3mg,47%)。1 H NMR(旋轉異構體(約1：1)之混合物)。Let N-((1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxabicyclo[3.2. 1]oct-4-yl)-N-methylacetamide (lo-1) (19 mg, 0.037 mmol), 1-methyl-1,4-cyclohexadiene (0.093 ml, 0.81 mmol) A mixture of 10% Pd/C (20 mg) and 2-propanol (2.5 ml) was stirred at 80 ° C for 3 hours. Water (0.2 ml) was added and the whole mixture was loaded onto a silicone and dried on a rotary evaporator. The product was purified on a silica gel column eluting with 4% to 15% methanol/dichloromethane to afford the title compound (4.3 mg, 47%). 1 H NMR (mixture of rotamers (about 1:1)).

旋轉異構體1：1 H NMR(甲醇-d4 )δ：5.20(s,1H),4.65(d,J=10.5Hz,1H),4.02-4.09(m,1H),3.89-3.98(m,2H),3.84(s,1H),3.78-3.82(m,1H),3.68(s,1H),3.11(s,3H),2.15(s,3H)。Rotamer 1: 1 H NMR (methanol-d 4 ) δ: 5.20 (s, 1H), 4.65 (d, J = 10.5 Hz, 1H), 4.02-4.09 (m, 1H), 3.89 - 3.98 (m) , 2H), 3.84 (s, 1H), 3.78-3.82 (m, 1H), 3.68 (s, 1H), 3.11 (s, 3H), 2.15 (s, 3H).

旋轉異構體2：1 H NMR(甲醇-d4 )δ：5.37(s,1H),4.02-4.09(m,1H),3.89-3.98(m,3H),3.84-3.87(m,1H),3.79-3.83(m,1H),3.71(d,J=8.2Hz,1H),2.98(s,3H),2.15(s,3H)。13 C NMR(甲醇-d4 )δ：175.4,104.6,85.8,71.3,69.7,66.2,62.3,59.1,28.8,22.7；LCMS(ES-)：0.41分鐘，246.2(M-H)- 。Rotamer 2: 1 H NMR (methanol-d 4 ) δ: 5.37 (s, 1H), 4.02-4.09 (m, 1H), 3.89-3.98 (m, 3H), 3.84-3.87 (m, 1H) , 3.79-3.83 (m, 1H), 3.71 (d, J = 8.2 Hz, 1H), 2.98 (s, 3H), 2.15 (s, 3H). 13 C NMR (methanol -d 4) δ: 175.4,104.6,85.8,71.3,69.7,66.2,62.3,59.1,28.8,22.7; LCMS (ES -): 0.41 minutes, 246.2 (MH) -.

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-N-甲基甲磺醯胺(30)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]- N-methylmethanesulfonamide (30)

令N-((1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-((苄氧基)甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)-N-甲基甲磺醯胺(l-o-2)(11mg,0.020毫莫耳)、1-甲基-1,4-環己二烯(0.093ml,0.81毫莫耳)、10% Pd/C(20mg)及2-丙醇(2.5ml)之混合物於80℃下經攪拌3小時。加入水(0.2ml)並令全體混合物載入矽膠且於旋轉蒸發器上乾燥。矽膠管柱層析(經4%至15%甲醇之二氯甲烷梯度溶液洗提)生成呈無色膠之標的化合物(2.9mg,51%)。1 H NMR(甲醇-d4 )δ：5.26(d,J=1.2Hz,1H),4.00-4.05(m,1H),3.92-3.96(m, 1H),3.89-3.91(m,1H),3.84(d,J=1.2Hz,1H),3.77-3.83(m,2H),3.68(d,J=7.8Hz,1H),3.35(s,3H),2.93(s,3H)；13 C NMR(甲醇-d4 )δ：106.1,85.5,71.5,69.7,65.9,62.6,62.2,37.8,30.4；LCMS(ES- )：0.42分鐘，282.0(M-H)- 。Let N-((1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-((benzyloxy)methyl)-6,8-dioxabicyclo[3.2. 1]oct-4-yl)-N-methylmethanesulfonamide (lo-2) (11 mg, 0.020 mmol), 1-methyl-1,4-cyclohexadiene (0.093 ml, 0.81 m) A mixture of 10% Pd/C (20 mg) and 2-propanol (2.5 ml) was stirred at 80 ° C for 3 hours. Water (0.2 ml) was added and the whole mixture was loaded onto a silicone and dried on a rotary evaporator. Chromatography (column elution with 4% to 15% methanol in dichloromethane) gave the title compound (2.9 mg, 51%). 1 H NMR (methanol-d 4 ) δ: 5.26 (d, J = 1.2 Hz, 1H), 4.40-4.05 (m, 1H), 3.92-3.96 (m, 1H), 3.89-3.91 (m, 1H), 3.84 (d, J = 1.2 Hz, 1H), 3.77-3.83 (m, 2H), 3.68 (d, J = 7.8 Hz, 1H), 3.35 (s, 3H), 2.93 (s, 3H); 13 C NMR (methanol-d 4 ) δ: 106.1, 85.5, 71.5, 69.7, 65.9, 62.6, 62.2, 37.8, 30.4; LCMS (ES - ): 0.42 min, 282.0 (MH) - .

[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]甲基胺甲酸三級丁酯(31)[(1S, 2R, 3R, 4R, 5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]methylamine Tert-butyl formate (31)

於微波小管(5ml)中對{(1S,2R,3R,4R,5S)-2,3-雙(苄氧基)-1-[(苄氧基)甲基]-6,8-二氧雜雙環[3.2.1]辛-4-基}甲基胺甲酸三級丁酯(l-o-3)(75mg,0.13毫莫耳)之2-丙醇(1.0ml)和四氫呋喃(0.5ml)溶液先後加入1-甲基-1,4-環己二烯(0.18ml,1.56毫莫耳)和10% Pd/C(50%濕重wt/wt,20.0mg)。該小管經密封並經加熱至80℃達4小時。經4小時後，TLC(10%甲醇/二氯甲烷)顯示反應未完全但生成所欲之產物。加入額外之1-甲基-1,4-環己二烯(0.18ml,1.6毫莫耳)並令反應物再經密封且經隔夜(18小時)加熱至80℃。經全部22小時後，令反應物經甲醇稀釋並經通過Life Sciences Acrodisc 25mm注射濾器過濾。令濾液經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈固體之標的化合物(29.0mg,73%)。方法C：3分鐘LRMS [M+Na=328]。化合物係2種旋轉異構體(約1：1)之混合物。Pair of {(1S,2R,3R,4R,5S)-2,3-bis(benzyloxy)-1-[(benzyloxy)methyl]-6,8-diox in a microwave vial (5ml) Heterobicyclo[3.2.1]oct-4-yl}methylaminecarboxylic acid tert-butyl butyl ester (lo-3) (75 mg, 0.13 mmol) of 2-propanol (1.0 ml) and tetrahydrofuran (0.5 ml) 1-Methyl-1,4-cyclohexadiene (0.18 ml, 1.56 mmol) and 10% Pd/C (50% wet weight wt/wt, 20.0 mg) were added in succession. The tube was sealed and heated to 80 °C for 4 hours. After 4 hours, TLC (10% methanol / dichloromethane) showed that the reaction was not complete but the desired product was formed. Additional 1-methyl-1,4-cyclohexadiene (0.18 ml, 1.6 mmol) was added and the reaction was resealed and heated to 80 ° C overnight (18 h). After all 22 hours, the reaction was diluted with MeOH and filtered thru a &lt The filtrate was concentrated under reduced pressure. The crude product was purified with EtOAc EtOAc (EtOAc) elute Method C: 3 minutes LRMS [M+Na=328]. The compound is a mixture of two rotamers (about 1:1).

旋轉異構體1：1 H NMR(甲醇-d4 )δ：5.22(br.s.,1H),4.19(d,J=10.6Hz,1H),4.00(d,J=10.6Hz,1H),3.90-3.95(m,2H),3.77-3.82(m,2H),3.67(d,J=7.6Hz,1H),2.94(s,3H),1.47(s,9H)。Rotamer 1: 1 H NMR (methanol-d 4 ) δ: 5.22 (br.s., 1H), 4.19 (d, J = 10.6 Hz, 1H), 4.00 (d, J = 10.6 Hz, 1H) , 3.90-3.95 (m, 2H), 3.77-3.82 (m, 2H), 3.67 (d, J = 7.6 Hz, 1H), 2.94 (s, 3H), 1.47 (s, 9H).

旋轉異構體2：1 H NMR(甲醇-d4 )δ：5.21(br.s.,1H),4.05-4.10(m,1H),4.00(d,J=10.6Hz,1H),3.90-3.95(m,2H),3.77-3.82(m,2H),3.67(d,J=7.6Hz,1H),2.94(s,3H),1.47(s,9H)。Rotamer 2: 1 H NMR (methanol-d 4 ) δ: 5.21. (br.s., 1H), 4.05-4.10 (m, 1H), 4.00 (d, J = 10.6 Hz, 1H), 3.90- 3.95 (m, 2H), 3.77-3.82 (m, 2H), 3.67 (d, J = 7.6 Hz, 1H), 2.94 (s, 3H), 1.47 (s, 9H).

(1S,2R,3R,4R,5S)-1-(羥基甲基)-4-(甲基胺基)-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二醇氫氯化物(32)(1S, 2R, 3R, 4R, 5S)-1-(hydroxymethyl)-4-(methylamino)-6,8-dioxabicyclo[3.2.1]octane-2,3-di Alcohol Hydrochloride (32)

對[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]甲基胺甲酸三級丁酯(31)(25.3mg,0.0829毫莫耳)之二氯甲烷(5.0ml)溶液加入4.0M氯化氫之二噁烷(0.518ml,2.07毫莫耳)溶液並令反應物於室溫下經攪拌48小時。經48小時後，令反應物於減壓下經濃縮。令粗產物經乙酸乙酯(5ml)沖洗以生成固體並經庚烷(10ml)稀釋且經減壓下濃縮以生成呈固體之標的化合物(30.0mg,130%)。方法C：3分鐘LRMS[M+1=206]。1 H NMR(甲醇-d4 )δ：5.63(s,1H),3.90-3.97(m,3H),3.84(s, 2H),3.78(d,J=8.2Hz,1H),3.10-3.20(m,1H),2.84(s,3H)。For [(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]methyl A solution of methylene chloride (31) (25.3 mg, 0.0829 mmol) in dichloromethane (5.0 ml) was added to a solution of 4.0 M hydrogen chloride in dioxane (0.518 ml, 2.07 mmol). Stir at room temperature for 48 hours. After 48 hours, the reaction was concentrated under reduced pressure. The crude product was washed with EtOAc (EtOAc) (EtOAc) Method C: 3 minutes LRMS [M+1 = 206]. 1 H NMR (methanol-d 4 ) δ: 5.63 (s, 1H), 3.90-3.97 (m, 3H), 3.84 (s, 2H), 3.78 (d, J = 8.2 Hz, 1H), 3.10-3.20 ( m, 1H), 2.84 (s, 3H).

N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-3)N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(15-phenyl-2,5,8,11,14-pentaoxapentadecane-1- Base)-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamidamine (le-3)

對N-[(1S,2R,6R,7R,8S)-1-(羥基甲基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(I-e-1)(1200mg,4.39毫莫耳)和13-碘-1-苯基-2,5,8,11-四氧雜十三烷(參閱文獻Synthetic Metals,162(23),2163-2170,2012；7000mg,17.76毫莫耳)之二氯甲烷(30.0ml)溶液先後加入硫酸氫四丁基銨(2290mg,6.60毫莫耳)和12.5M氫氧化鈉水溶液(30.0ml,380毫莫耳)。令反應物於室溫下經攪拌64小時。經64小時後，令反應物經水和二氯甲烷稀釋。分離相層且水層再經二氯甲烷萃取2次。令結合之有機層經1N氫氯酸溶液沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮。對所生成之粗產物加入乙酸乙酯(50ml)並經攪拌30分鐘。令所生成之沉澱物經過濾。令濾液經減壓下濃縮。令粗產物經CombiFlash Rf(ISCO RediSep Gold 80g矽膠管柱；先經0至100%乙酸乙酯/庚烷梯度洗提且隨後立即經0至20%甲 醇/二氯甲烷梯度洗提)純化以生成標的化合物(1267mg,53.5%)。方法C：1.5分鐘LRMS[M+Na=562]。1 H NMR(甲醇-d4 )δ：7.13-7.45(m,5H),5.22(d,J=1.6Hz,1H),4.55(s,2H),4.30(d,J=5.9Hz,1H),4.15(t,J=6.4Hz,1H),3.89-3.97(m,2H),3.85(d,J=7.8Hz,1H),3.73-3.79(m,2H),3.58-3.71(m,16H),1.98(s,3H),1.48(s,3H),1.33(s,3H)。For N-[(1S,2R,6R,7R,8S)-1-(hydroxymethyl)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~ 2,6~]undecyl-7-yl]acetamide (Ie-1) (1200 mg, 4.39 mmol) and 13-iodo-1-phenyl-2,5,8,11-tetraoxa Tridecane (See Synthetic Metals, 162 (23), 2163-2170, 2012; 7000 mg, 17.76 mmol) in dichloromethane (30.0 ml) solution followed by tetrabutylammonium hydrogen sulfate (2290 mg, 6.60 mmol) and 12.5 M aqueous sodium hydroxide solution (30.0 ml, 380 mmol). The reaction was allowed to stir at room temperature for 64 hours. After 64 hours, the reaction was diluted with water and dichloromethane. The phase layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed with 1N aqueous hydrochloric acid, dried over magnesium sulfate and filtered and evaporated. Ethyl acetate (50 ml) was added to the obtained crude product and stirred for 30 min. The resulting precipitate was filtered. The filtrate was concentrated under reduced pressure. The crude product was purified via a CombiFlash Rf (ISCO RediSep Gold 80 g cartridge) eluted with a gradient from 0 to 100% ethyl acetate / heptane and then immediately eluted with 0 to 20% methanol / dichloromethane gradient to yield The title compound (1267 mg, 53.5%). Method C: 1.5 minutes LRMS [M+Na=562]. 1 H NMR (methanol-d 4 ) δ: 7.13 - 7.45 (m, 5H), 5.22 (d, J = 1.6 Hz, 1H), 4.55 (s, 2H), 4.30 (d, J = 5.9 Hz, 1H) , 4.15 (t, J = 6.4 Hz, 1H), 3.89 - 3.97 (m, 2H), 3.85 (d, J = 7.8 Hz, 1H), 3.73 - 3.79 (m, 2H), 3.58 - 3.71 (m, 16H) ), 1.98 (s, 3H), 1.48 (s, 3H), 1.33 (s, 3H).

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(33)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(15-phenyl-2,5,8,11,14-pentaoxapentadecan-1-yl) )-6,8-dioxabicyclo[3.2.1]oct-4-yl]acetamidamine (33)

令N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-3)(60.0mg,0.11毫莫耳)之乙酸(4.0ml)、甲醇(1.0ml)及水(1.0ml)溶液經隔夜加熱至70℃。經18小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮。令該粗產物經CombiFlash Rf(RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(42.5mg,77%)。方法C：3分鐘LRMS[M+1=500]。1 H NMR(甲醇-d4 )δ：7.14-7.45(m,5H),5.21(s,1H),4.55(s,2H), 3.92-4.01(m,2H),3.88(d,J=4.3Hz,1H),3.77(d,J=7.8Hz,1H),3.70(dd,J=9.8,3.9Hz,1H),3.58-3.68(m,18H),1.98(s,3H)。Let N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(15-phenyl-2,5,8,11,14-pentaoxapentadecan-1 -yl)-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamidamine (le-3) (60.0 mg, 0.11 mmol) A solution of acetic acid (4.0 ml), methanol (1.0 ml) and water (1.0 ml) was heated to 70 ° C overnight. After 18 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc (EtOAc) elute. Method C: 3 minutes LRMS [M+1 = 500]. 1 H NMR (methanol-d 4 ) δ: 7.14 - 7.45 (m, 5H), 5.21 (s, 1H), 4.55 (s, 2H), 3.92-4.01 (m, 2H), 3.88 (d, J = 4.3) Hz, 1H), 3.77 (d, J = 7.8 Hz, 1H), 3.70 (dd, J = 9.8, 3.9 Hz, 1H), 3.58-3.68 (m, 18H), 1.98 (s, 3H).

N-[(1S,2R,6R,7R,8S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-2)N-[(1S,2R,6R,7R,8S)-1-(13-azido-2,5,8,11-tetraoxatridec-1-yl)-4,4-dimethyl Base-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamidamine (le-2)

於5℃(冰/水)下對N-[(1S,2R,6R,7R,8S)-1-(羥基甲基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(I-e-1)(10.0g,36.59毫莫耳，1.0當量)之N,N-二甲基甲醯胺(200ml)攪拌溶液加入氫氧化鉀(8.21g,146.37毫莫耳，4當量)。經加入後，令反應混合物於5℃下經攪拌30分鐘。隨後將1-疊氮基-2-{2-[2-(2-碘乙氧基)乙氧基]乙氧基}乙烷(36.13g,109.78毫莫耳，3.0當量)於5℃(冰/水)下加入至該反應混合物中。令該反應混合物於5℃(冰/水)下經攪拌30分鐘並令該反應混合物經加熱至27℃並於27℃下經攪拌18小時。經18小時後，將該反應混合物倒入至冰/水中且經二氯甲烷(400ml)萃取3次。令結合之有機層經水(400ml)和鹽水(500ml)沖洗3次，置於硫酸鈉上乾燥且經過濾和濃縮以生成粗產物。令該粗產物經矽膠層析(經二氯甲烷：甲醇=100：1至40：1洗提)純化 以生成呈無色油之標的化合物(10.0g,57.6%)。方法C：3分鐘LRMS[M+45(甲酸)=519]。1 H NMR(甲醇-d4 )δ：5.23(d,J=2.0Hz,1H),4.31(d,J=5.9Hz,1H),4.16(t,J=6.6Hz,1H),3.93-3.97(m,1H),3.90-3.93(m,J=2.0Hz,1H),3.86(d,J=7.8Hz,1H),3.78(d,J=3.9Hz,1H),3.75(d,J=1.6Hz,1H),3.61-3.71(m,14H),3.37(t,J=4.9Hz,2H),1.98(s,3H),1.49(s,3H),1.34(s,3H)。N-[(1S,2R,6R,7R,8S)-1-(hydroxymethyl)-4,4-dimethyl-3,5,9,11-tetra at 5 ° C (ice/water) O, N-dimethyl group of oxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (Ie-1) (10.0 g, 36.59 mmol, 1.0 eq.) To a solution of the formamide (200 ml) was added potassium hydroxide (8.21 g, 146.37 mmol, 4 eq.). After the addition, the reaction mixture was stirred at 5 ° C for 30 minutes. Then 1-azido-2-{2-[2-(2-iodoethoxy)ethoxy]ethoxy}ethane (36.13 g, 109.78 mmol, 3.0 eq.) at 5 ° C ( Add to the reaction mixture under ice/water). The reaction mixture was stirred at 5 ° C (ice/water) for 30 min and the reaction mixture was heated to 27 ° C and stirred at 27 ° C for 18 h. After 18 hours, the reaction mixture was poured into ice/water and extracted with dichloromethane (400 ml). The combined organic layers were washed 3 times with water (400 mL) and brine (500 mL), dried over sodium sulfate and filtered and concentrated to give crude. The crude product was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc Method C: 3 minutes LRMS [M+45 (carboxylic acid) = 519]. 1 H NMR (methanol-d 4 ) δ: 5.23 (d, J = 2.0 Hz, 1H), 4.31 (d, J = 5.9 Hz, 1H), 4.16 (t, J = 6.6 Hz, 1H), 3.93-3.97 (m, 1H), 3.90-3.93 (m, J = 2.0 Hz, 1H), 3.86 (d, J = 7.8 Hz, 1H), 3.78 (d, J = 3.9 Hz, 1H), 3.75 (d, J = 1.6 Hz, 1H), 3.61-3.71 (m, 14H), 3.37 (t, J = 4.9 Hz, 2H), 1.98 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H).

N-[(1S,2R,3R,4R,5S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(34)N-[(1S,2R,3R,4R,5S)-1-(13-azido-2,5,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy -6,8-dioxabicyclo[3.2.1]oct-4-yl]acetamidamine (34)

令N-[(1S,2R,6R,7R,8S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-2)(82.0mg,0.17毫莫耳)之乙酸(6.0ml)、甲醇(1.45ml)及水(1.45ml)溶液經隔夜加熱至70℃。經18小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈油之標的化合物(43.3mg,58%)。方法C：3分鐘LRMS[M-1=433]。1 H NMR(甲醇-d4 )δ：5.21(d,J=0.8Hz,1H),3.98(d,J=9.8Hz, 1H),3.94(d,J=9.8Hz,1H),3.89(d,J=4.3Hz,1H),378(d,J=7.8Hz,1H),3.72(dd,J=10.1,4.3Hz,1H),3.61-3.69(m,16H),3.38(t,J=4.9Hz,2H),1.99(s,3H)。Let N-[(1S,2R,6R,7R,8S)-1-(13-azido-2,5,8,11-tetraoxatridec-1-yl)-4,4-di Methyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamidamine (le-2) (82.0 mg, 0.17 mmol) A solution of acetic acid (6.0 ml), methanol (1.45 ml) and water (1.45 ml) was heated to 70 ° C overnight. After 18 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure. The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) Method C: 3 minutes LRMS [M-1 = 433]. 1 H NMR (methanol-d 4 ) δ: 5.21 (d, J = 0.8 Hz, 1H), 3.98 (d, J = 9.8 Hz, 1H), 3.94 (d, J = 9.8 Hz, 1H), 3.89 (d) , J = 4.3 Hz, 1H), 378 (d, J = 7.8 Hz, 1H), 3.72 (dd, J = 10.1, 4.3 Hz, 1H), 3.61-3.69 (m, 16H), 3.38 (t, J = 4.9 Hz, 2H), 1.99 (s, 3H).

N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(2,5,8,11-四氧雜十四碳-13-烯-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-4)N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(2,5,8,11-tetraoxatetradecyl-13-en-1-yl)- 3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamidamine (le-4)

對N-[(1S,2R,6R,7R,8S)-1-(羥基甲基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(I-e-1)(50.0mg,0.18毫莫耳)和3-{2-[2-(2-碘乙氧基)乙氧基]乙氧基}丙-1-烯(參閱文獻Organic Letters,5(11),1887-1890,2003；139.0mg,0.463毫莫耳)之二氯甲烷(1.5ml)溶液先後加入硫酸氫四丁基銨(95.3mg,0.275毫莫耳)和12.5M氫氧化鈉水溶液(0.75ml,9.4毫莫耳)。令反應物於室溫下經隔夜攪拌。經18小時後，令反應物經水和二氯甲烷稀釋。分離相層且令水層再經二氯甲烷萃取2次。令結合之有機層經1N氫氯酸溶液和水沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮。令所生成之粗產物經乙酸乙酯(5ml)稀釋並令所生成之沉澱物於室溫下經攪拌30分鐘。令沉澱物經過濾並令濾餅經乙酸乙酯(2×5ml)沖洗。令濾液經減壓下濃縮。令粗產物經 CombiFlash Rf(ISCO RediSep Gold 4g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化。該管柱隨後經0至20%甲醇/二氯甲烷梯度溶液洗提以生成標的化合物(13.6mg,17%)。方法C：1.5分鐘LRMS[M+Na=468]。1 H NMR(甲醇-d4 )δ：5.92(ddt,J=16.8,10.9,5.7Hz,1H),5.28(dd,J=17.4,1.4Hz,1H),5.23(d,J=1.6Hz,1H),5.16(dd,J=10.3,1.0Hz,1H),4.31(d,J=5.9Hz,1H),4.15(t,J=6.4Hz,1H),4.02(d,J=5.5Hz,2H),3.89-3.97(m,2H),3.86(d,J=7.8Hz,1H),3.73-3.80(m,2H),3.56-3.72(m,12H),1.98(s,3H),1.49(s,3H),1.34(s,3H)。For N-[(1S,2R,6R,7R,8S)-1-(hydroxymethyl)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~ 2,6~]undecyl-7-yl]acetamide (Ie-1) (50.0 mg, 0.18 mmol) and 3-{2-[2-(2-iodoethoxy)ethoxy Ethoxy}prop-1-ene (See Organic Letters, 5 (11), 1887-1890, 2003; 139.0 mg, 0.463 mmol) in dichloromethane (1.5 ml) followed by the addition of tetrabutylammonium hydrogen sulfate (95.3 mg, 0.275 mmol). And 12.5 M aqueous sodium hydroxide solution (0.75 ml, 9.4 mmol). The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and dichloromethane. The phase layer was separated and the aqueous layer was extracted twice more dichloromethane. The combined organic layers were washed with 1N aqueous hydrochloric acid and water, dried over magnesium sulfate and filtered and evaporated. The resulting crude product was diluted with ethyl acetate (5 mL) and the resulting precipitate was stirred at room temperature for 30 min. The precipitate was filtered and the filter cake was washed with ethyl acetate (2×5 mL). The filtrate was concentrated under reduced pressure. The crude product was purified via a CombiFlash Rf (ISCO RediSep Gold 4g cartridge) eluting from 0 to 100% ethyl acetate / heptane gradient. The column was then eluted with a gradient of 0 to 20% methanol / dichloromethane to give the title compound (13.6 mg, 17%). Method C: 1.5 minutes LRMS [M+Na=468]. 1 H NMR (methanol-d 4 ) δ: 5.92 (ddt, J = 16.8, 10.9, 5.7 Hz, 1H), 5.28 (dd, J = 17.4, 1.4 Hz, 1H), 5.23 (d, J = 1.6 Hz, 1H), 5.16 (dd, J = 10.3, 1.0 Hz, 1H), 4.31 (d, J = 5.9 Hz, 1H), 4.15 (t, J = 6.4 Hz, 1H), 4.02 (d, J = 5.5 Hz, 2H), 3.89-3.97 (m, 2H), 3.86 (d, J = 7.8 Hz, 1H), 3.73-3.80 (m, 2H), 3.56-3.72 (m, 12H), 1.98 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H).

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(2,5,8,11-四氧雜十四碳-13-烯-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(35)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(2,5,8,11-tetraoxatetradecyl-13-en-1-yl)-6 ,8-Dioxabicyclo[3.2.1]oct-4-yl]acetamidamine (35)

令N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(2,5,8,11-四氧雜十四碳-13-烯-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-4)(13.0mg,0.029毫莫耳)之乙酸(1.0ml)、甲醇(0.25ml)及水(0.25ml)溶液經隔夜加熱至70℃。經18小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮。令該粗產物經CombiFlash Rf(RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成標的化合物(6.5mg,55%)。方法 C：3分鐘LRMS[M+1=406]。1 H NMR(甲醇-d4 )δ：5.80-6.09(m,1H),5.28(dd,J=17.2,1.6Hz,1H),5.21(d,J=0.8Hz,1H),5.16(dd,J=10.5,1.2Hz,1H),4.02(d,J=5.5Hz,2H),3.98(d,J=9.8Hz,1H),3.95(d,J=10.1Hz,1H),3.89(d,J=3.9Hz,1H),3.78(d,J=8.2Hz,1H),3.71(dd,J=10.0,4.5Hz,1H),3.57-3.68(m,14H),1.99(s,3H)。Let N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(2,5,8,11-tetraoxatetradecyl-13-en-1-yl) -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (le-4) (13.0 mg, 0.029 mmol) A solution of acetic acid (1.0 ml), methanol (0.25 ml) and water (0.25 ml) was heated overnight to 70 °C. After 18 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure. The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) Method C: 3 minutes LRMS [M+1 = 406]. 1 H NMR (methanol-d 4 ) δ: 5.80-6.09 (m, 1H), 5.28 (dd, J = 17.2, 1.6 Hz, 1H), 5.21. (d, J = 0.8 Hz, 1H), 5.16 (dd, J = 10.5, 1.2 Hz, 1H), 4.02 (d, J = 5.5 Hz, 2H), 3.98 (d, J = 9.8 Hz, 1H), 3.95 (d, J = 10.1 Hz, 1H), 3.89 (d, J = 3.9 Hz, 1H), 3.78 (d, J = 8.2 Hz, 1H), 3.71 (dd, J = 10.0, 4.5 Hz, 1H), 3.57-3.68 (m, 14H), 1.99 (s, 3H).

N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(2,5,8,11-四氧雜十四碳-13-炔-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-5)N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(2,5,8,11-tetraoxatetradecyl-13-yn-1-yl)- 3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamidamine (le-5)

對N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(I-e-1)(100.0mg,0.366毫莫耳)和3-{2-[2-(2-碘乙氧基)乙氧基]乙氧基}丙-1-炔(參閱文獻Synthesis,(10),1639-1644,2010；425.0mg,1.43毫莫耳)之二氯甲烷(3ml)溶液先後加入硫酸氫四丁基銨(191mg，0.550毫莫耳)和12.5M氫氧化鈉水溶液(1.5ml,19毫莫耳)。令反應物於室溫下經隔夜攪拌。經18小時後，令反應物經水和二氯甲烷稀釋。分離相層且令水層再經二氯甲烷萃取2次。令結合之有機 層經1N氫氯酸溶液和水沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮。令所生成之粗產物經乙酸乙酯(20ml)稀釋並令所生成之沉澱物於室溫下經攪拌30分鐘。令沉澱物經過濾並令濾餅經乙酸乙酯(2×15ml)沖洗。令濾液經減壓下濃縮。令粗產物經CombiFlash Rf(ISCO RediSep Gold 12g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化。該管柱隨後經0至20%甲醇/二氯甲烷梯度溶液洗提以生成標的化合物(70.0mg,43%)。方法C：1.5分鐘LRMS[M+Na=466]。1 H NMR(甲醇-d4 )δ：5.23(d,J=1.6Hz,1H),4.31(d,J=5.9Hz,1H),4.19(d,J=2.3Hz,2H),4.16(t,J=6.4Hz,1H),3.90-3.97(m,2H),3.86(d,J=7.8Hz,1H),3.74-3.79(m,2H),3.60-3.72(m,12H),2.85(t,J=2.3Hz,1H),1.98(s,3H),1.49(s,3H),1.34(s,3H)。For N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(15-phenyl-2,5,8,11,14-pentaoxapentadecan-1 -yl)-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (Ie-1) (100.0 mg, 0.366 mmol) Ear) and 3-{2-[2-(2-iodoethoxy)ethoxy]ethoxy}prop-1-yne (See Synthesis, (10), 1639-1644, 2010; 425.0 mg, 1.43 mmol) in dichloromethane (3 ml) with tetrabutylammonium hydrogen sulfate (191 mg, 0.550 mmol) and 12.5 M. Aqueous sodium hydroxide (1.5 ml, 19 mmol). The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and dichloromethane. The phase layer was separated and the aqueous layer was extracted twice more dichloromethane. The combined organic layers were washed with 1N aqueous hydrochloric acid and water, dried over magnesium sulfate and filtered and evaporated. The resulting crude product was diluted with ethyl acetate (20 mL) and then evaporated. The precipitate was filtered and the filter cake was washed with ethyl acetate (2×15 mL). The filtrate was concentrated under reduced pressure. The crude product was purified via a CombiFlash Rf (ISCO RediSep Gold 12g cartridge) eluting from 0 to 100% ethyl acetate / heptane gradient. The column was then eluted with a gradient of 0 to 20% methanol / dichloromethane to give the title compound (70.0 mg, 43%). Method C: 1.5 minutes LRMS [M+Na=466]. 1 H NMR (methanol-d 4 ) δ: 5.23 (d, J = 1.6 Hz, 1H), 4.31 (d, J = 5.9 Hz, 1H), 4.19 (d, J = 2.3 Hz, 2H), 4.16 (t) , J = 6.4 Hz, 1H), 3.90-3.97 (m, 2H), 3.86 (d, J = 7.8 Hz, 1H), 3.74 - 3.79 (m, 2H), 3.60 - 3.72 (m, 12H), 2.85 ( t, J = 2.3 Hz, 1H), 1.98 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H).

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(2,5,8,11-四氧雜十四碳-13-炔-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(36)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(2,5,8,11-tetraoxatetradecyl-13-yn-1-yl)-6 ,8-Dioxabicyclo[3.2.1]oct-4-yl]acetamidamine (36)

令N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(2,5,8,11-四氧雜十四碳-13-炔-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-5)(70.0mg,0.16毫莫耳)之乙酸(4.0ml)、甲醇(1.0ml)及水(1.0ml)溶液經隔夜加熱至70℃。經18小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次 經甲苯稀釋並經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(57.6mg,90%)。方法C：3分鐘LRMS[M+1=404]。1 H NMR(甲醇-d4 )δ：5.22(s,1H),4.19(d,J=1.8Hz,2H),3.98(d,J=10.0Hz,1H),3.94(d,J=10.0Hz,1H),3.89(d,J=4.1Hz,1H),3.78(d,J=8.2Hz,1H),3.71(dd,J=10.0,4.1Hz,1H),3.60-3.69(m,14H),2.86(s,1H),1.99(s,3H)。Let N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(2,5,8,11-tetraoxatetradecyl-13-yn-1-yl) -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (le-5) (70.0 mg, 0.16 mmol) A solution of acetic acid (4.0 ml), methanol (1.0 ml) and water (1.0 ml) was heated overnight to 70 °C. After 18 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc EtOAc. Method C: 3 minutes LRMS [M+1 = 404]. 1 H NMR (methanol-d 4 ) δ: 5.22 (s, 1H), 4.19 (d, J = 1.8 Hz, 2H), 3.98 (d, J = 10.0 Hz, 1H), 3.94 (d, J = 10.0 Hz) , 1H), 3.89 (d, J = 4.1 Hz, 1H), 3.78 (d, J = 8.2 Hz, 1H), 3.71 (dd, J = 10.0, 4.1 Hz, 1H), 3.60-3.69 (m, 14H) , 2.86 (s, 1H), 1.99 (s, 3H).

N-[(1S,2R,3R,4R,5S)-1-(13-胺基-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(37)N-[(1S,2R,3R,4R,5S)-1-(13-Amino-2,5,8,11-tetraoxatridecyl-1-yl)-2,3-dihydroxy- 6,8-Dioxabicyclo[3.2.1]oct-4-yl]acetamidamine (37)

令N-[(1S,2R,3R,4R,5S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(34)(40.0mg,0.092毫莫耳)之乙醇(2ml)溶液通過H立方體(H-cube)(條件：觸媒(10% Pd/C(30×4mm)；流速：1ml/分鐘；溫度：室溫；壓力=全部H2 )。經通過該H立方體後，收集溶液並經減壓下濃縮以生成呈膠之標的化合物(17.2mg,46%)。方法C：3分鐘LRMS[M+1=409]。1 H NMR(甲醇-d4 )δ：5.21(s,1H),3.92-4.00(m,2H),3.89(d,J=3.9Hz,1H),3.78(d,J=8.2Hz,1H),3.69-3.74(m,1H),3.61-3.69(m,14H),3.56(t,J=5.1Hz,2H), 2.85(t,J=5.1Hz,2H),1.99(s,3H)。Let N-[(1S,2R,3R,4R,5S)-1-(13-azido-2,5,8,11-tetraoxatridec-1-yl)-2,3-di A solution of hydroxy-6,8-dioxabicyclo[3.2.1]oct-4-yl]acetamide (34) (40.0 mg, 0.092 mmol) in ethanol (2 ml) was passed through H-cube (Condition: catalyst (10% Pd/C (30 × 4 mm); flow rate: 1 ml/min; temperature: room temperature; pressure = all H 2 ). After passing through the H cube, the solution was collected and concentrated under reduced pressure. The compound was obtained as a gel (17.2 mg, 46%). Method C: 3 mins LRMS [M+1=409]. 1 H NMR (methanol-d 4 ) δ: 5.21. (s, 1H), 3.92-4. (m, 2H), 3.89 (d, J = 3.9 Hz, 1H), 3.78 (d, J = 8.2 Hz, 1H), 3.69 - 3.74 (m, 1H), 3.61-3.69 (m, 14H), 3.56 ( t, J = 5.1 Hz, 2H), 2.85 (t, J = 5.1 Hz, 2H), 1.99 (s, 3H).

N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(13-羥基-2,5,8,11-四氧雜十三烷-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(38)N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(13-hydroxy-2,5,8,11-tetraoxatridec-1-yl)-6 ,8-Dioxabicyclo[3.2.1]oct-4-yl]acetamidamine (38)

令N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺(33)(43mg,0.086毫莫耳)溶解於甲醇(2ml)之溶液通過H立方體(條件：觸媒：20%氫氧化鈀/C(30×4mm)；流速：1ml/分鐘；溫度：60℃；壓力=全部H2 )。經通過該H立方體後，收集溶液並經減壓下濃縮以生成標的化合物(32.2mg,91%)。1 H NMR(甲醇-d4 )δ：5.21(s,1H),3.98(d,J=9.4Hz,1H),3.95(d,J=10.1Hz,1H),3.89(d,J=4.3Hz,1H),3.78(d,J=8.2Hz,1H),3.71(dd,J=9.8,4.3Hz,1H),3.61-3.69(m,16H),3.54-3.59(m,2H),1.99(s,3H)。13 C NMR(甲醇-d4 )δ：174.1,102.6,84.3,73.8,72.5,71.7,71.7(2),71.6,71.5,71.4,70.5,70.2,69.0,62.4,56.4,22.7。Let N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(15-phenyl-2,5,8,11,14-pentaoxapentadecan-1- a solution of 6,8-dioxabicyclo[3.2.1]oct-4-yl]acetamide (33) (43 mg, 0.086 mmol) dissolved in methanol (2 ml) through H cube (conditions: Catalyst: 20% palladium hydroxide / C (30 x 4 mm); flow rate: 1 ml / min; temperature: 60 ° C; pressure = all H 2 ). After passing through the H-cube, the solution was collected and concentrated under reduced pressure to give the title compound (32.2 mg, 91%). 1 H NMR (methanol-d 4 ) δ: 5.21 (s, 1H), 3.98 (d, J = 9.4 Hz, 1H), 3.95 (d, J = 10.1 Hz, 1H), 3.89 (d, J = 4.3 Hz) , 1H), 3.78 (d, J = 8.2 Hz, 1H), 3.71 (dd, J = 9.8, 4.3 Hz, 1H), 3.61-3.69 (m, 16H), 3.54-3.59 (m, 2H), 1.99 ( s, 3H). 13 C NMR (methanol-d 4 ) δ: 174.1, 102.6, 84.3, 73.8, 72.5, 71.7, 71.7 (2), 71.6, 71.5, 71.4, 70.5, 70.2, 69.0, 62.4, 56.4, 22.7.

N-[(1S,2R,6R,7R,8S)-1-(13-羥基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-6)N-[(1S,2R,6R,7R,8S)-1-(13-hydroxy-2,5,8,11-tetraoxatridec-1-yl)-4,4-dimethyl- 3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (le-6)

令N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-3)(2.897g,5.37毫莫耳)溶解於甲醇(150ml)之溶液通過H立方體(條件：觸媒：10% Pd/C(30×4mm)；流速：1ml/分鐘；溫度：60℃；壓力=全部H2 )。經通過該H立方體後，收集溶液並經減壓下濃縮以生成呈膠之標的化合物(2.5g,100%)。方法C：1.5分鐘LRMS[M+1=450]。1 H NMR(甲醇-d4 )δ：5.23(d,J=1.6Hz,1H),4.31(d,J=5.9Hz,1H),4.16(t,J=6.4Hz,1H),3.89-3.97(m,2H),3.86(d,J=7.8Hz,1H),3.74-3.80(m,2H),3.60-3.71(m,14H),3.53-3.59(m,2H),1.98(s,3H),1.49(s,3H),1.34(s,3H)。Let N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(15-phenyl-2,5,8,11,14-pentaoxapentadecan-1 -yl)-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamidamine (le-3) (2.897 g, 5.37 mmol) The ear dissolved in methanol (150 ml) was passed through an H cube (condition: catalyst: 10% Pd/C (30 x 4 mm); flow rate: 1 ml/min; temperature: 60 ° C; pressure = all H 2 ). After passing through the H-cube, the solution was collected and concentrated under reduced pressure to give a compound (2.5 g, 100%) as a gel. Method C: 1.5 minutes LRMS [M+1 = 450]. 1 H NMR (methanol-d 4 ) δ: 5.23 (d, J = 1.6 Hz, 1H), 4.31 (d, J = 5.9 Hz, 1H), 4.16 (t, J = 6.4 Hz, 1H), 3.89 - 3.97 (m, 2H), 3.86 (d, J = 7.8 Hz, 1H), 3.74-3.80 (m, 2H), 3.60-3.71 (m, 14H), 3.53-3.59 (m, 2H), 1.98 (s, 3H) ), 1.49 (s, 3H), 1.34 (s, 3H).

N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(13-側氧基-2,5,8,11-四氧雜十三烷-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-6a)N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(13- oxo-2,5,8,11-tetraoxatridec-1-yl) )-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (le-6a)

對N-[(1S,2R,6R,7R,8S)-1-(13-羥基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環 [6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-6)(175mg,0.389毫莫耳)之二氯甲烷(5.0ml)溶液加入Dess-Martin反應劑(354mg,0.584毫莫耳)以生成混合物。經約30分鐘後，反應物轉變成幾乎呈均質。經3小時後，令反應混合物經二氯甲烷稀釋並經通過寅氏鹽管塞且經二氯甲烷沖洗。令濾液經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 24g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化。令含有所欲之產物的管經減壓下濃縮。令所生成之產物經二氯甲烷(4ml)和***(10ml)稀釋以生成白色沉澱物。令該溶液經傾析並令固體經二氯甲烷(2ml)和***(8ml)稀釋且經再次傾析。令經傾析之溶液通過含有0.45μm耐隆膜之Life Science Acrodisc 25mm注射管濾器。令所收集之溶液經減壓下濃縮以生成呈膠之標的化合物(65.0mg,37%)。方法C：3分鐘LRMS[M+1=448]。1 H NMR(氯仿-d)δ：9.74(s,1H),5.63(d,J=9.0Hz,1H),5.34(d,J=1.6Hz,1H),4.23(d,J=5.9Hz,1H),4.17(s,2H),4.09-4.15(m,1H),4.01(t,J=6.2Hz,1H),3.97(d,J=10.1Hz,1H),3.77-3.85(m,3H),3.68-3.76(m,5H),3.61-3.68(m,7H),2.03(s,3H),1.56(s,3H),1.36(s,3H)。For N-[(1S,2R,6R,7R,8S)-1-(13-hydroxy-2,5,8,11-tetraoxatridec-1-yl)-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (le-6) (175 mg, 0.389 mmol) A solution of methyl chloride (5.0 ml) was added to a Dess-Martin reagent (354 mg, 0.584 mmol) to give a mixture. After about 30 minutes, the reactants turned into almost homogeneous. After 3 hours, the reaction mixture was diluted with dichloromethane and filtered thru abr. The filtrate was concentrated under reduced pressure. The crude product was purified via a CombiFlash Rf (RediSep Gold 24 g cartridge) eluting with 0 to 20% methanol / dichloromethane gradient. The tube containing the desired product was concentrated under reduced pressure. The resulting product was diluted with dichloromethane (4 mL) and diethyl ether (10 mL) to yield a white precipitate. The solution was decanted and the solid was diluted with dichloromethane (2 mL) and diethyl ether (EtOAc) The decanted solution was passed through a Life Science Acrodisc 25 mm syringe filter containing a 0.45 [mu]m LAMP. The collected solution was concentrated under reduced pressure to give compound (65.0 mg, 37%). Method C: 3 minutes LRMS [M+1 = 448]. 1 H NMR (chloroform-d) δ: 9.74 (s, 1H), 5.63 (d, J = 9.0 Hz, 1H), 5.34 (d, J = 1.6 Hz, 1H), 4.23 (d, J = 5.9 Hz, 1H), 4.17 (s, 2H), 4.09-4.15 (m, 1H), 4.01 (t, J = 6.2 Hz, 1H), 3.97 (d, J = 10.1 Hz, 1H), 3.77-3.85 (m, 3H) ), 3.68-3.76 (m, 5H), 3.61-3.68 (m, 7H), 2.03 (s, 3H), 1.56 (s, 3H), 1.36 (s, 3H).

1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-酸(38A)1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl] -2,5,8,11-tetraoxatridecane-13-acid (38A)

令N-[(1S,2R,6R,7R,8S)-4,4-二甲基-1-(13-側氧基-2,5,8,11-四氧雜十三烷-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-6a)(60.0mg,0.13毫莫耳)之四氫呋喃/三級丁醇(1.5ml/1.5ml)溶液與2-甲基-2-丁烯(1.0ml)反應並隨後藉由玻璃吸量管與亞氯酸鈉(169.4mg,2.01毫莫耳)和磷酸鈉(250.0mg,2.58毫莫耳)(單價一水合物；250mg,2.58毫莫耳)之水(1.5ml)溶液反應。令反應物於室溫下經攪拌24小時。經24小時後，將反應混合物倒入至水中並經乙酸乙酯萃取3次。丟棄有機層。令水層經減壓下濃縮並令所生成之粗產物溶解於甲醇(10ml)和二氯甲烷(100ml)且令所生成之混合物經過濾。令濾液經減壓下濃縮。令所生成之產物溶解於甲醇(5ml)和二氯甲烷(50ml)且令所生成之混合物經過濾。令濾液經CombiFlash Rf(RediSep 4g矽膠管柱；經0至100%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物鈉鹽(40mg，無，67%)。LRMS[M+1=424]；1 H NMR(甲醇-d4 )δ：5.24(s,1H),4.14(s,2H),3.97(d,J=10.1Hz,2H),3.90(d,J=3.9Hz,1H),3.81(d,J=7.8Hz,1H),3.63-3.77(m,15H),2.01(s,3H)。Let N-[(1S,2R,6R,7R,8S)-4,4-dimethyl-1-(13-sided oxy-2,5,8,11-tetraoxatridecane-1- Base)-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (le-6a) (60.0 mg, 0.13 mmol) A solution of tetrahydrofuran/tertiary butanol (1.5 ml/1.5 ml) was reacted with 2-methyl-2-butene (1.0 ml) and then passed through a glass pipette with sodium chlorite (169.4 mg, 2.01 mil). Mohr) was reacted with a solution of sodium phosphate (250.0 mg, 2.58 mmol) (monovalent monohydrate; 250 mg, 2.58 mmol) in water (1.5 ml). The reaction was allowed to stir at room temperature for 24 hours. After 24 hours, the reaction mixture was poured into water and extracted with ethyl acetate three times. Discard the organic layer. The aqueous layer was concentrated under reduced pressure and the obtained crude product was dissolved in methanol (10 ml) and dichloromethane (100 ml) and the resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The product thus obtained was dissolved in methanol (5 ml) and dichloromethane (50 ml) and the resulting mixture was filtered. The filtrate was purified via a CombiFlash Rf (RediSep 4g cartridge) eluting with 0 to 100% methanol/dichloromethane gradient to yield the compound sodium salt (40 mg, abs, 67%). LRMS[M+1=424]; 1 H NMR (methanol-d 4 ) δ: 5.24 (s, 1H), 4.14 (s, 2H), 3.97 (d, J = 10.1 Hz, 2H), 3.90 (d, J = 3.9 Hz, 1H), 3.81 (d, J = 7.8 Hz, 1H), 3.63 - 3.77 (m, 15H), 2.01 (s, 3H).

甲磺酸1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基酯(l-e-7)1-[(1S,2R,6R,7R,8S)-7-(ethylammonium)-4,4-dimethyl-3,5,9,11-tetraoxatricyclomethane [6.2] .1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl ester (le-7)

對甲磺酸1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基酯(l-e-6)(1117mg,2.49毫莫耳)之二氯甲烷(12.4ml)溶液加入三乙胺(1.05ml,7.45毫莫耳)並使用冰浴冷卻至0℃且隨後加入甲磺醯氯(0.232ml,2.98毫莫耳)。令反應物緩慢回溫至室溫並於室溫下經攪拌1.5小時。經1.5小時後，令該反應物經水驟冷並經萃取。分離相層並令水層再經二氯甲烷萃取。令結合之有機層經鹽水沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮以生成呈粗產物之標的化合物(1300.0mg,99.2%)。方法C：3分鐘LRMS[M+Na=550]。1 H NMR(甲醇-d4 )δ：5.23(d,J=2.0Hz,1H),4.34-4.40(m,2H),4.31(d,J=5.9Hz,1H),4.15(t,J=6.4Hz,1H),3.89-3.97(m,2H),3.86(d,J=7.8Hz,1H),3.72-3.81(m,4H),3.59-3.71(m,12H),3.11(s,3H),1.98(s,3H),1.48(s,3H),1.34(s,3H)。1-[(1S,2R,6R,7R,8S)-7-(ethylammonium)-4,4-dimethyl-3,5,9,11-tetraoxatricyclomethanesulfonate [ 6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl ester (le-6) (1117 mg, 2.49 mmol) A solution of dichloromethane (12.4 ml) was added triethylamine (1.05 mL, 7.45 mmol) and cooled to 0 &lt;0&gt;C using an ice bath and then methanesulfonium chloride (0.232 ml, 2.98 mmol). The reaction was slowly warmed to room temperature and stirred at room temperature for 1.5 hours. After 1.5 hours, the reaction was quenched with water and extracted. The phase layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered and evaporated. Method C: 3 minutes LRMS [M+Na=550]. 1 H NMR (methanol-d 4 ) δ: 5.23 (d, J = 2.0 Hz, 1H), 4.34 - 4.40 (m, 2H), 4.31 (d, J = 5.9 Hz, 1H), 4.15 (t, J = 6.4 Hz, 1H), 3.89-3.97 (m, 2H), 3.86 (d, J = 7.8 Hz, 1H), 3.72-3.81 (m, 4H), 3.59-3.71 (m, 12H), 3.11 (s, 3H) ), 1.98 (s, 3H), 1.48 (s, 3H), 1.34 (s, 3H).

乙硫羥酸S-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}酯(l-e-8)Ethyl thiol S-{1-[(1S,2R,6R,7R,8S)-7-(acetamido)-4,4-dimethyl-3,5,9,11-tetraoxa Tricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl} ester (le-8)

對甲磺酸1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基酯(l-e-7)(125.0mg,0.237毫莫耳)之N,N-二甲基甲醯胺(2ml)溶液加入硫代乙酸鉀(135mg,1.18毫莫耳)並令反應物於室溫下經攪拌64小時。經64小時後，令反應物經水稀釋並經乙酸乙酯萃取3次。令結合之有機層經鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(95.2mg,79.2%)。方法C：3分鐘LRMS[M+Na=530]。1 H NMR(甲醇-d4 )δ：5.23(d,J=1.6Hz,1H),4.31(d,J=5.9Hz,1H),4.16(t,J=6.4Hz,1H),3.90-3.97(m,2H),3.86(d,J=7.8Hz,1H),3.74-3.79(m,2H),3.55-3.72(m,14H),3.08(t,J=6.6Hz,2H),2.32(s,3H),1.98(s,3H),1.49(s,3H),1.34(s,3H)。1-[(1S,2R,6R,7R,8S)-7-(ethylammonium)-4,4-dimethyl-3,5,9,11-tetraoxatricyclomethanesulfonate [ 6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl ester (le-7) (125.0 mg, 0.237 mmol) A solution of N,N-dimethylformamide (2 ml) was added to potassium thioacetate (135 mg, 1.18 mmol) and the mixture was stirred at room temperature for 64 hours. After 64 hours, the reaction was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and evaporated. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc. Method C: 3 minutes LRMS [M+Na=530]. 1 H NMR (methanol-d 4 ) δ: 5.23 (d, J = 1.6 Hz, 1H), 4.31 (d, J = 5.9 Hz, 1H), 4.16 (t, J = 6.4 Hz, 1H), 3.90 - 3.97 (m, 2H), 3.86 (d, J = 7.8 Hz, 1H), 3.74 - 3.79 (m, 2H), 3.55 - 3.72 (m, 14H), 3.08 (t, J = 6.6 Hz, 2H), 2.32 ( s, 3H), 1.98 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H).

乙硫羥酸S-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}酯(39)Ethylthiol S-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1 ]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl} ester (39)

令乙硫羥酸S-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}酯(l-e-8)(81.0mg,0.16毫莫耳)之乙酸(6.0ml)、甲醇(1.45ml)及水(1.45ml)溶液經隔夜加熱至70℃。經18小時後，令反應物冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(53.7mg,72%)。方法C：3分鐘LRMS[M+1=468]。1 H NMR(甲醇-d4 )δ：5.23(s,1H),4.00(d,J=9.8Hz,1H),3.97(d,J=9.8Hz,1H),3.91(d,J=4.3Hz,1H),3.80(d,J=7.8Hz,1H),3.73(dd,J=10.1,4.3Hz,1H),3.63-3.70(m,14H),3.60(t,J=6.6Hz,2H),3.10(t,J=6.4Hz,2H),2.34(s,3H),2.01(s,3H)。Ethyl thiocyanate S-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl-3,5,9,11-tetraoxy Heterotricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl} ester (le-8) (81.0 mg A solution of 0.16 mmol of acetic acid (6.0 ml), methanol (1.45 ml) and water (1.45 ml) was heated overnight to 70 °C. After 18 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure. The crude material was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc EtOAc Method C: 3 minutes LRMS [M+1 = 468]. 1 H NMR (methanol-d 4 ) δ: 5.23 (s, 1H), 4.00 (d, J = 9.8 Hz, 1H), 3.97 (d, J = 9.8 Hz, 1H), 3.91 (d, J = 4.3 Hz) , 1H), 3.80 (d, J = 7.8 Hz, 1H), 3.73 (dd, J = 10.1, 4.3 Hz, 1H), 3.63-3.70 (m, 14H), 3.60 (t, J = 6.6 Hz, 2H) , 3.10 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 2.01 (s, 3H).

N-{(1S,2R,3R,4R,5S)-2,3-二羥基-1-[13-(吡啶-2-基二甲硫基)-2,5,8,11-四氧雜十三烷-1-基]-6,8-二氧雜雙環[3.2.1]辛-4-基}乙醯胺(40)N-{(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-[13-(pyridin-2-yldimethylthio)-2,5,8,11-tetraoxa Tridec-1-yl]-6,8-dioxabicyclo[3.2.1]oct-4-yl}acetamidamine (40)

對乙硫羥酸S-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}酯(39)(50mg,0.11毫莫耳)之甲醇(3ml) 溶液加入0.5M甲氧化鈉之甲醇溶液(1.28ml,0.642毫莫耳)並令反應物於室溫下經攪拌45分鐘。經45分鐘後，加入乙酸(42mg,0.70毫莫耳，0.040ml)並經攪拌10分鐘。隨後將該甲醇溶液逐滴加入至2,2'-二硫烷二基二吡啶(35.3mg,0.160毫莫耳)於甲醇(2ml)和乙酸(1ml)之混合物中之攪拌溶液。令反應物於室溫下經攪拌2小時。經2小時後，令反應物於減壓下經濃縮。令粗產物經CombiFlash Rf(RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成標的化合物(31.4mg,55%)。方法C：3分鐘LRMS[M+Na=557]。1 H NMR(甲醇-d4 )δ：8.39(d,J=4.3Hz,1H),7.94(d,J=8.2Hz,1H),7.83(td,J=7.8,1.6Hz,1H),7.22(dd,J=6.8,5.3Hz,1H),5.2l(s,1H),3.92-4.00(m,2H),3.88(d,J=4.3Hz,1H),3.77(d,J=7.8Hz,1H),3.71(t,J=6.0Hz,3H),3.59-3.67(m,12H),3.52-3.58(m,2H),3.02(t,J=6.0Hz,2H),1.99(s,3H)。For ethionic acid S-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2. 1] Oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}ester (39) (50 mg, 0.11 mmol) in methanol (3 ml) A solution of sodium oxide in methanol (1.28 mL, 0.642 mmol) was obtained and the mixture was stirred at room temperature for 45 min. After 45 minutes, acetic acid (42 mg, 0.70 mmol, 0.040 mL) was added and stirred for 10 min. The methanol solution was then added dropwise to a stirred solution of 2,2'-disulfanediylbipyridine (35.3 mg, 0.160 mmol) in a mixture of methanol (2 ml) and acetic acid (1 ml). The reaction was allowed to stir at room temperature for 2 hours. After 2 hours, the reaction was concentrated under reduced pressure. The crude product was purified with EtOAc (EtOAc) eluting Method C: 3 minutes LRMS [M+Na=557]. 1 H NMR (methanol-d 4 ) δ: 8.39 (d, J = 4.3 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.83 (td, J = 7.8, 1.6 Hz, 1H), 7.22 (dd, J = 6.8, 5.3 Hz, 1H), 5.2 l (s, 1H), 3.92-4.00 (m, 2H), 3.88 (d, J = 4.3 Hz, 1H), 3.77 (d, J = 7.8 Hz) , 1H), 3.71 (t, J = 6.0 Hz, 3H), 3.59-3.67 (m, 12H), 3.52-3.58 (m, 2H), 3.02 (t, J = 6.0 Hz, 2H), 1.99 (s, 3H).

{1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}胺甲酸三級丁酯(l-f-3){1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-yl}carbamic acid tert-butyl butyl ester ( Lf-3)

對合成化合物(I-f-3)，參閱文獻Journal of Organic Chemistry,73(14),5602-5605,2008。For the synthesis of the compound (I-f-3), see Journal of Organic Chemistry, 73 (14), 5602-5605, 2008.

1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-胺氫氯酸(l-p-1)1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-amine hydrochloride (l-p-1)

對{1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}胺甲酸三級丁酯(l-f-3)(3000mg,8.945毫莫耳)之二氯甲烷(45ml)溶液加入4.0M氯化氫之二噁烷溶液(20ml,89.4毫莫耳)並令反應物於室溫下經攪拌18小時。經18小時後，令反應物於減壓下經濃縮以生成油。加入乙酸乙酯(20ml)至粗混合物並令所生成之混合物經攪拌。加入庚烷(20ml)並令混合物於室溫下經攪拌2小時。令產物經過濾並令濾餅經乙酸乙酯沖洗且經抽真空乾燥2小時以生成標的化合物(2140mg,88%)。1 H NMR(甲醇-d4 )δ：4.25(s,6H),3.72(s,6H),2.97(s,3H)。1,3-Di(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-yl}carbamic acid tert-butyl butyl ester A solution of (lf-3) (3000 mg, 8.945 mmol) in dichloromethane (45 ml) was added EtOAc (EtOAc m. . After 18 hours, the reaction was concentrated under reduced pressure to give an oil. Ethyl acetate (20 ml) was added to the crude mixture and the resulting mixture was stirred. Heptane (20 ml) was added and the mixture was stirred at room temperature for 2 h. The product was filtered and the filter cake was washed with ethyl acetate and dried under vacuum for 2 hr to give the title compound (2140 mg, 88%). 1 H NMR (methanol-d 4 ) δ: 4.25 (s, 6H), 3.72 (s, 6H), 2.97 (s, 3H).

[6-({1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}胺基)-6-側氧基己基]胺甲酸苄酯(l-q-1)[6-({1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-yl}amino) -6-oxooxyhexyl] benzyl carbamate (lq-1)

對6-{[(芾氧基)羰基]胺基}己酸(2910mg,11.0毫莫耳)之N,N-二甲基甲醯胺(4ml)和四氫呋喃(20.0ml)溶液加入N-(3-二甲基胺基丙基)-N’-乙基碳二醯亞胺氫氯化物(l-p-1)(2150mg,11.0毫莫耳)和1-羥基苯並***(1480mg,11.0毫莫耳)並令反應物於室溫下經攪拌1小時，於該期間該反應物轉變呈均質。將純1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-胺氫氯酸(2130mg,7.84毫莫耳)一次加入至該攪拌反應混合物並隨後加入N,N-二異丙基乙胺(5.46ml,31.4毫莫耳)且令反應物經加熱至60℃達24小時。令該反應物冷卻至室溫並經攪拌24小時。令該反應物經水(150ml)驟冷並經乙酸乙酯萃取。令水層再經乙酸乙酯沖洗1次。令結合之有機層經鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 80g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成呈油之標的化合物(3250mg,86%)，其係經靜置固化。方法C：MassLynx\Acid_3.0Min.olp-LRMS[M+1=483]。1 H NMR(甲醇-d4 )δ：7.10-7.46(m,5H),5.06(s,2H),4.14(d,J=2.0Hz,6H),3.79(s,6H),3.03-3.20(m,2H),2.83(t,J=2.1Hz,3H),2.18(t,J=7.2Hz,2H),1.59(quin,J=7.3Hz,2H),1.44-1.54(m,2H),1.28-1.40(m,2H)。For 6-{[(decyloxy)carbonyl]amino}hexanoic acid (2910 mg, 11.0 mmol) of N,N-dimethylformamide (4 ml) and tetrahydrofuran (20.0 ml) were added to N-(3-dimethylaminopropyl)-N'-ethyl carbon Diimine imine hydrochloride (lp-1) (2150 mg, 11.0 mmol) and 1-hydroxybenzotriazole (1480 mg, 11.0 mmol) and the reaction was stirred at room temperature for 1 hour. The reactant transition was homogeneous during this period. Pure 1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-amine hydrochloride (2130 mg, 7.84) To the stirred reaction mixture was added in one portion and then N,N-diisopropylethylamine (5.46 ml, 31.4 mmol) was added and the mixture was heated to 60 ° C for 24 hours. The reaction was allowed to cool to room temperature and stirred for 24 h. The reaction was quenched with water (150 mL)EtOAc. The aqueous layer was washed once more with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered and evaporated. The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) elute Method C: MassLynx\Acid_3.0 Min.olp-LRMS [M+1=483]. 1 H NMR (methanol-d 4 ) δ: 7.10-7.46 (m, 5H), 5.06 (s, 2H), 4.14 (d, J = 2.0 Hz, 6H), 3.79 (s, 6H), 3.03 - 3.20 ( m, 2H), 2.83 (t, J = 2.1 Hz, 3H), 2.18 (t, J = 7.2 Hz, 2H), 1.59 (quin, J = 7.3 Hz, 2H), 1.44-1.54 (m, 2H), 1.28-1.40 (m, 2H).

6-(吡啶-2-基二甲硫基)己酸(l-r-1)6-(pyridin-2-yldimethylthio)hexanoic acid (l-r-1)

令2,2'-二硫烷二基二吡啶(1490mg,6.75毫莫耳)之乙醇(12.0ml)和乙酸(0.291ml)之混合溶液於氮氣下經攪拌並隨後逐滴加入6-硫烷基己酸(1000.0mg,6.75毫莫耳)之乙酸乙酯(6.0ml)溶液。令反應物於室溫下經攪拌2小時。經2小時後，令反應物於減壓下經濃縮。令粗產物經CombiFlash Rf(RediSep Gold 40g矽膠管柱；經0至100%乙酸乙酯(2%乙酸改質劑)/庚烷梯度洗提)純化以生成粗標的化合物(1170mg)。令該粗產物再經CombiFlash Rf(RediSep Gold 40g矽膠管柱；經0至100%乙酸乙酯(2%乙酸改質劑)/庚烷梯度洗提)純化以生成呈油之標的化合物(544mg,31%)。2,2'-disulfanediyldipyridine (1490 mg, 6.75 mmol) of a mixed solution of ethanol (12.0 ml) and acetic acid (0.291 ml) were stirred under nitrogen and then 6-thioalkylhexanoic acid was added dropwise A solution of (1000.0 mg, 6.75 mmol) in ethyl acetate (6.0 mL). The reaction was allowed to stir at room temperature for 2 hours. After 2 hours, the reaction was concentrated under reduced pressure. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc (EtOAc) The crude product was purified by CombiFlash Rf (RediSep Gold 40 g cartridge) eluting with 0 to 100% ethyl acetate (2% acetic acid modifier) / heptane gradient to give the oil as a compound (544 mg, 31%).

1-{[6-(吡啶-2-基二甲硫基)己醯基]氧基}吡咯啶-2,5-二酮(l-s-1)1-{[6-(pyridin-2-yldimethylthio)hexanyl]oxy}pyrrolidine-2,5-dione (l-s-1)

對6-(吡啶-2-基二甲硫基)己酸(l-r-1)(705mg,2.2毫莫耳)之N,N-二甲基甲醯胺(4ml)溶液先後加入N-羥基琥珀醯亞胺(306mg,2.66毫莫耳)和N-(3-二甲基胺基丙基)-N’-乙基碳二醯亞胺氫氯化物(520mg,2.66毫莫耳)。令反應物於室溫下經隔夜攪拌。次晨，令該反應物經水驟冷並經 二氯甲烷萃取3次。令結合之有機層經飽和碳酸氫鈉溶液和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 40g管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成標的化合物(364mg,47%)。方法C：1.5分鐘LRMS[M+1=355]。1 H NMR(甲醇-d4 )δ：8.39(d,J=4.7Hz,1H),7.85-7.90(m,1H),7.77-7.84(m,1H),7.21(dd,J=6.6,5.5Hz,1H),2.77-2.90(m,6H),2.61(t,J=7.2Hz,2H),1.63-1.83(m,4H),1.46-1.59(m,2H)。N-hydroxyamyl amber was added to a solution of 6-(pyridin-2-yldimethylthio)hexanoic acid (lr-1) (705 mg, 2.2 mmol) in N,N-dimethylformamide (4 ml) Yttrium (306 mg, 2.66 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (520 mg, 2.66 mmol). The reaction was allowed to stir overnight at room temperature. The next morning, the reaction was quenched with water and extracted with dichloromethane three times. The combined organic layers were washed with aq. sodium hydrogen sulfate and brine, dried over sodium sulfate The crude product was purified with EtOAc EtOAc EtOAc (EtOAc) Method C: 1.5 minutes LRMS [M+1 = 355]. 1 H NMR (methanol-d 4 ) δ: 8.39 (d, J = 4.7 Hz, 1H), 7.85-7.90 (m, 1H), 7.77-7.84 (m, 1H), 7.21. (dd, J = 6.6, 5.5 Hz, 1H), 2.77-2.90 (m, 6H), 2.61 (t, J = 7.2 Hz, 2H), 1.63-1.83 (m, 4H), 1.46-1.59 (m, 2H).

N-{1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}-6-(吡啶-2-基二甲硫基)己醯胺(l-t-1)N-{1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-yl}-6-(pyridine -2-yldimethylthio)hexylamine (lt-1)

對1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-胺氫氯酸(l-p-1)(100.0mg,0.324毫莫耳)之N,N-二甲基甲醯胺(2.0ml)溶液加入N,N-二異丙基乙胺(0.339ml,1.95毫莫耳)並經攪拌10分鐘且隨後一次加入1-{[6-(吡啶-2-基二甲硫基)己醯基]氧基}吡咯啶-2,5-二酮(l-s-1)(138mg,0.389毫莫耳)並令反應物經加熱至60℃達16小時。經16小時後，令該反應物經水稀釋並經乙酸乙酯萃取3次。令結合之有機層經水和鹽水沖洗，置於硫酸鈉上乾燥 且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 12g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成呈膠之標的化合物(66.7mg,43%)。方法C：1.5分鐘LRMS[M+Na=497]。1 H NMR(甲醇-d4 )δ：8.39(d,J=4.7Hz,1H),7.85-7.90(m,1H),7.78-7.84(m,1H),7.19-7.25(m,1H),4.06-4.23(m,6H),3.72-3.84(m,6H),2.78-2.87(m,5H),2.12-2.20(m,2H),1.71(quin,J=7.3Hz,2H),1.57(quin,J=7.3Hz,2H),1.36-1.50(m,2H)。1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-amine hydrochloride (lp-1) (100.0 mg, 0.324 mmol) of N,N-dimethylformamide (2.0 ml) was added N,N-diisopropylethylamine (0.339 ml, 1.95 mmol) and stirred for 10 min. And then added 1-{[6-(pyridin-2-yldimethylthio)hexanyl]oxy}pyrrolidine-2,5-dione (ls-1) (138 mg, 0.389 mmol) The reaction was allowed to warm to 60 ° C for 16 hours. After 16 hours, the reaction was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate and filtered and evaporated. The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) elute Method C: 1.5 minutes LRMS [M+Na=497]. 1 H NMR (methanol-d 4 ) δ: 8.39 (d, J = 4.7 Hz, 1H), 7.85-7.90 (m, 1H), 7.78-7.84 (m, 1H), 7.19-7.25 (m, 1H), 4.06-4.23 (m, 6H), 3.72-3.84 (m, 6H), 2.78-2.87 (m, 5H), 2.12-2.20 (m, 2H), 1.71 (quin, J = 7.3 Hz, 2H), 1.57 ( Quin, J = 7.3 Hz, 2H), 1.36-1.50 (m, 2H).

1-{[4-(苄氧基)丁醯基]氧基}吡咯啶-2,5-二酮(l-u-1)1-{[4-(benzyloxy)butanyl]oxy}pyrrolidine-2,5-dione (l-u-1)

對4-(芾氧基)丁酸(1000mg,3.77毫莫耳)之N,N-二甲基甲醯胺(7.54ml)溶液先後加入N-羥基琥珀醯亞胺(521mg,4.52毫莫耳)和N-(3-二甲基胺基丙基)-N’-乙基碳二醯亞胺氫氯化物(885mg,4.52毫莫耳)。令反應物於室溫下經隔夜攪拌。次晨，令該反應物經水驟冷並經二氯甲烷萃取3次。令結合之有機層經飽和碳酸氫鈉溶液和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 40g管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成標的化合物(1098mg,100%)。方法C：1.5分鐘LRMS[M+Na=314]。1 H NMR(甲醇-d4 )δ：7.11-7.50(m,5H),4.51(s,2H),3.56(t, J=6.0Hz,2H),2.81(s,4H),2.73(t,J=7.2Hz,2H),1.99(quin,J=6.6Hz,2H)。N-Hydroxysuccinimide (521 mg, 4.52 mmol) was added to a solution of 4-(decyloxy)butanoic acid (1000 mg, 3.77 mmol) in N,N-dimethylformamide (7.54 ml). And N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (885 mg, 4.52 mmol). The reaction was allowed to stir overnight at room temperature. The next morning, the reaction was quenched with water and extracted with dichloromethane three times. The combined organic layers were washed with aq. sodium hydrogen sulfate and brine, dried over sodium sulfate The crude product was purified with EtOAc EtOAc EtOAc (EtOAc) Method C: 1.5 minutes LRMS [M+Na=314]. 1 H NMR (methanol-d 4 ) δ: 7.11-7.50 (m, 5H), 4.51 (s, 2H), 3.56 (t, J = 6.0 Hz, 2H), 2.81 (s, 4H), 2.73 (t, J = 7.2 Hz, 2H), 1.99 (quin, J = 6.6 Hz, 2H).

4-(苄氧基)-N-{1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}丁醯胺(l-v-1)4-(Benzyloxy)-N-{1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propane-2 -yl}butylamine (lv-1)

對1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-胺三氟乙酸(l-p-1)(750.0mg,1.62毫莫耳)之N,N-二甲基甲醯胺(5ml)溶液加入N,N-二異丙基乙胺(1.69ml,9.71毫莫耳)並經攪拌10分鐘且隨後加入1-{[4-(苄氧基)丁醯基]氧基}吡咯啶-2,5-二酮(l-u-1)(566mg,1.94毫莫耳)之N,N-二甲基甲醯胺(1ml)溶液並令反應物經加熱至60℃達72小時。經72小時後，令該反應物經水稀釋並經乙酸乙酯萃取3次。令結合之有機層經水和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 24g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成呈膠之標的化合物(495mg，無，74%)。方法C：1.5分鐘LRMS[M+1=412]。1 H NMR(甲醇-d4 )δ：7.21-7.41(m,5H),4.51(s,2H),4.12(d,J=2.3Hz,6H),3.78(s,6H),3.51(t,J=6.2Hz,2H),2.82(t,J=2.3Hz,3H),2.28(t,J=7.2Hz,2H),1.79-1.94 (m,2H)。1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-amine trifluoroacetic acid (lp-1) (750.0 mg, 1.62 mmol) of N,N-dimethylformamide (5 ml) was added N,N-diisopropylethylamine (1.69 ml, 9.71 mmol) and stirred for 10 min. Subsequent addition of 1-{[4-(benzyloxy)butanyl]oxy}pyrrolidin-2,5-dione (lu-1) (566 mg, 1.94 mmol) of N,N-dimethylformamidine A solution of the amine (1 ml) and the reaction was heated to 60 °C for 72 hours. After 72 hours the reaction was diluted with water and extracted with EtOAc EtOAc. The combined organic layers were washed with water and brine, dried over sodium sulfate and filtered and evaporated. The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) elute Method C: 1.5 minutes LRMS [M+1 = 412]. 1 H NMR (methanol-d 4 ) δ: 7.21 - 7.41 (m, 5H), 4.51 (s, 2H), 4.12 (d, J = 2.3 Hz, 6H), 3.78 (s, 6H), 3.51 (t, J = 6.2 Hz, 2H), 2.82 (t, J = 2.3 Hz, 3H), 2.28 (t, J = 7.2 Hz, 2H), 1.79-1.94 (m, 2H).

(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺甲酸三級丁酯(l-w-1)(1,3-bis[(1-S1-[(1S,2R,6R,7R,8S)-7-(acetamido)-4,4-dimethyl-3,5,9,11 -tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2 ,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4 -Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxa Alkyl 13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)carbamic acid tert-butyl butyl ester (lw-1)

對配備攪拌棒之圓底燒瓶(50ml)載入{1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}胺甲酸三級丁酯(l-f-3)(305.0mg,0.909毫莫耳)並先後加入N-[(1S,2R,6R,7R,8S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷- 7-基]乙醯胺(l-e-2)(1433.0mg,3.020毫莫耳)之三級丁醇(12ml)溶液、水(5ml)及純抗壞血酸鈉(1840mg,9.09毫莫耳)並令反應物經氮氣清洗10分鐘。加入硫酸銅(II)(147mg,0.909毫莫耳)之去離子水(1ml)溶液並於室溫下經攪拌24小時。經24小時後，藉由將反應混合物加入至飽和氯化銨溶液(30ml)和濃氫氧化銨溶液(3ml)使反應驟冷且經二氯甲烷(20ml)萃取3次。令結合之有機層置於硫酸鎂上乾燥並經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 80g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈白色泡沫之標的化合物(789.0mg，無，49.3%)。方法C：1.5分鐘LRMS[M+45-1=1804]。1 H NMR(甲醇-d4 )δ：8.00(s,3H),5.23(d,J=1.6Hz,3H),4.51-4.63(m,12H),4.29(d,J=5.9Hz,3H),4.16(t,J=6.4Hz,3H),3.87-3.96(m,12H),3.84(d,J=7.8Hz,3H),3.73-3.80(m,6H),3.64-3.72(m,12H),3.54-3.63(m,30H),1.98(s,9H),1.48(s,9H),1.40(s,9H),1.33(s,9H)。Loading a round bottom flask (50 ml) equipped with a stir bar into {1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl] Propyl-2-yl}amine carboxylic acid tert-butyl butyl ester (lf-3) (305.0 mg, 0.909 mmol) followed by N-[(1S,2R,6R,7R,8S)-1-(13-stack) Nitrogen-2,5,8,11-tetraoxatridecyl-1-yl)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2 , 6~] undecane-7-yl]acetamide (le-2) (1433.0 mg, 3.020 mmol) in a solution of tertiary butanol (12 ml), water (5 ml) and pure sodium ascorbate (1840 mg, 9.09 millimoles) and the reaction was purged with nitrogen for 10 minutes. A solution of copper (II) sulfate (147 mg, 0.909 mmol) in deionized water (1 ml) was added and stirred at room temperature for 24 hours. After 24 hours, the reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. The combined organic layers were dried over magnesium sulfate and filtered and evaporated. The crude product was purified with EtOAc EtOAc (EtOAc) elute Method C: 1.5 minutes LRMS [M+45-1 = 1804]. 1 H NMR (methanol-d 4 ) δ: 8.00 (s, 3H), 5.23 (d, J = 1.6 Hz, 3H), 4.51-4.63 (m, 12H), 4.29 (d, J = 5.9 Hz, 3H) , 4.16 (t, J = 6.4 Hz, 3H), 3.87-3.96 (m, 12H), 3.84 (d, J = 7.8 Hz, 3H), 3.73-3.80 (m, 6H), 3.64 - 3.72 (m, 12H) ), 3.54-3.63 (m, 30H), 1.98 (s, 9H), 1.48 (s, 9H), 1.40 (s, 9H), 1.33 (s, 9H).

N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙 -2-基)-6-(吡啶-2-基二甲硫基)己醯胺(l-x-1)N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl-3,5,9 ,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1 ,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethinyl)-4 ,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxa Tridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propyl -2-yl)-6-(pyridin-2-yldimethylthio)hexylamine (l-x-1)

對N-{1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}-6-(吡啶-2-基二甲硫基)己醯胺(1-t-1)(66.0mg,0.14毫莫耳)和N-[(1S,2R,6R,7R,8S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-2)(219mg,0.459毫莫耳)之三級丁醇(2ml)溶液加入水(0.5ml；去離子水)。加入抗壞血酸鈉(84.3mg,0.417毫莫耳)固體並令反應混合物經氮氣清洗5分鐘且隨後加入硫酸銅(II)(6.73mg,0.0417毫莫耳)之水(0.5ml；去離子水)溶液並於室溫下經攪拌24小時。藉由將反應混合物加入至飽和氯化銨溶液(20ml)和濃氫氧化銨溶液(2ml)使反應驟冷並經二氯甲烷(15ml)萃取3次。令結合之有機層經鹽水沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮。令粗產物經 CombiFlash Rf(RediSep Gold 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成不純之標的化合物(105.0mg，無，40%)。令該粗產物(105.0mg)再經CombiFlash Rf(RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(94.5mg,36%)。方法C：MassLynx\Acid_3.0Min.olp-LRMS[M+Na=1921]。1 H NMR(甲醇-d4 )δ：8.38(d,J=4.7Hz,1H),7.97(s,3H),7.82-7.88(m,1H),7.78-7.81(m,1H),7.20(t,J=5.9Hz,1H),5.23(s,3H),4.52-4.62(m,12H),4.29(d,J=5.9Hz,3H),4.15(t,J=6.4Hz,3H),3.86-3.96(m,12H),3.81-3.85(m,3H),3.72-3.80(m,12H),3.54-3.71(m,36H),2.79(t,J=7.2Hz,2H),2.16(t,J=7.2Hz,2H),1.98(s,9H),1.64-1.73(m,2H),1.50-1.57(m,2H),1.48(s,9H),1.42(d,J=6.6Hz,2H),1.32(s,9H)。For N-{1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy)methyl]propan-2-yl}-6-( Pyridin-2-yldimethylthio)hexylamine (1-t-1) (66.0 mg, 0.14 mmol) and N-[(1S,2R,6R,7R,8S)-1-(13- Azido-2,5,8,11-tetraoxatridec-1-yl)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~ A solution of 2,6-]undecyl-7-yl]acetamide (le-2) (219 mg, 0.459 mmol) in tributylbutanol (2 ml) was added to water (0.5 ml; deionized water). Sodium ascorbate (84.3 mg, 0.417 mmol) solid was added and the reaction mixture was purged with nitrogen for 5 min and then copper (II) sulfate (6.73 mg, 0.0417 mmol) water (0.5 ml; deionized water) solution was added. It was stirred at room temperature for 24 hours. The reaction was quenched by EtOAc (3 mL)EtOAcEtOAcEtOAc The combined organic layers were washed with brine, dried over magnesium sulfate and filtered and evaporated. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc (EtOAc) elute. The crude product (105.0 mg) was purified by EtOAc (EtOAc) eluting eluting Method C: MassLynx\Acid_3.0 Min.olp-LRMS [M+Na=1921]. 1 H NMR (methanol-d 4 ) δ: 8.38 (d, J = 4.7 Hz, 1H), 7.97 (s, 3H), 7.82-7.88 (m, 1H), 7.78-7.81 (m, 1H), 7.20 ( t, J = 5.9 Hz, 1H), 5.23 (s, 3H), 4.52-4.62 (m, 12H), 4.29 (d, J = 5.9 Hz, 3H), 4.15 (t, J = 6.4 Hz, 3H), 3.86-3.96 (m, 12H), 3.81-3.85 (m, 3H), 3.72-3.80 (m, 12H), 3.54-3.71 (m, 36H), 2.79 (t, J = 7.2 Hz, 2H), 2.16 ( t, J = 7.2 Hz, 2H), 1.98 (s, 9H), 1.64-1.73 (m, 2H), 1.50-1.57 (m, 2H), 1.48 (s, 9H), 1.42 (d, J = 6.6 Hz) , 2H), 1.32 (s, 9H).

{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸苄酯(l-y-1){6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl-3,5 ,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H -1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino) -4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetra Oxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl} Benzyl carbamate (ly-1)

對配備攪拌棒之圓底燒瓶(250ml)載入[6-({1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}胺基)-6-側氧基己基]胺甲酸苄酯(l-q-1)(880.0mg,1.82毫莫耳)並先後加入N-[(1S,2R,6R,7R,8S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]乙醯胺(l-e-2)(3075.0mg,6.8毫莫耳)之三級丁醇(26ml)溶液、水(12ml)及純抗壞血酸鈉(3690mg,18.2毫莫耳)且令反應物經氮氣清洗10分鐘。加入硫酸銅(II)(294mg,1.82毫莫耳)之水(1ml)溶液並於室溫下經攪拌24小時。經24小時後，藉由將反應混合物加入至飽和氯化銨溶液(50ml)和濃氫氧化銨溶液(5ml)使反應驟冷並經二氯甲烷(45ml)萃取3次。令結合之有機層置於硫酸鎂上乾燥並經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 80g矽膠管柱；經0至 20%甲醇/二氯甲烷梯度洗提)純化以生成呈固體之標的化合物(1890.0mg,54.4%)和不純之標的化合物。令該粗產物(1270mg,36.5%)經CombiFlash Rf(RediSep Gold 80g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成標的化合物(607.0mg,17.5%)。標的化合物之總產率2.497g(72%)。方法C：3分鐘LRMS[M+1=1907]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),7.21-7.47(m,5H),5.25(d,J=1.6Hz,3H),5.07(s,2H),4.53-4.62(m,12H),4.31(d,J=5.9Hz,3H),4.18(t,J=6.4Hz,3H),3.88-3.98(m,12H),3.85(d,J=7.8Hz,3H),3.74-3.81(m,12H),3.53-3.71(m,36H),3.10(q,J=6.2Hz,2H),2.18(t,J=7.2Hz,2H),2.00(s,9H),1.53-1.65(m,2H),1.50(s,11H),1.34(s,11H)。Loading [6-({1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yn-1-yloxy) in a round bottom flask (250 ml) equipped with a stir bar Benzyl methyl]propan-2-yl}amino)-6-oxo-oxyhexyl] amide (lq-1) (880.0 mg, 1.82 mmol) and N-[(1S, 2R, 6R,7R,8S)-1-(13-azido-2,5,8,11-tetraoxatridecyl-1-yl)-4,4-dimethyl-3,5,9, 11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]acetamide (le-2) (3075.0 mg, 6.8 mmol) of tertiary butanol (26 ml) Solution, water (12 ml) and pure sodium ascorbate (3690 mg, 18.2 mmol) and the reaction was purged with nitrogen for 10 min. A solution of copper (II) sulfate (294 mg, 1.82 mmol) in water (1 ml) was added and stirred at room temperature for 24 hours. After 24 hours, the reaction was quenched with EtOAc EtOAc (EtOAc) The combined organic layers were dried over magnesium sulfate and filtered and evaporated. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc EtOAc. The crude product (1270 mg, 36.5%) was purified eluting with EtOAc (EtOAc) The total yield of the title compound was 2.497 g (72%). Method C: 3 minutes LRMS [M+1 = 1907]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 7.21 - 7.47 (m, 5H), 5.25 (d, J = 1.6 Hz, 3H), 5.07 (s, 2H), 4.53-4.62 ( m, 12H), 4.31 (d, J = 5.9 Hz, 3H), 4.18 (t, J = 6.4 Hz, 3H), 3.88-3.98 (m, 12H), 3.85 (d, J = 7.8 Hz, 3H), 3.74-3.81 (m, 12H), 3.53-3.71 (m, 36H), 3.10 (q, J = 6.2 Hz, 2H), 2.18 (t, J = 7.2 Hz, 2H), 2.00 (s, 9H), 1.53 -1.65 (m, 2H), 1.50 (s, 11H), 1.34 (s, 11H).

N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-6-(吡啶-2-基二甲硫基)己醯胺(41)N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy Methyl}propan-2-yl)-6-(pyridin-2-yldimethylthio)hexylamine (41)

令N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-6-(吡啶-2-基二甲硫基)己醯胺(I-x-1)(94.5mg,0.0498毫莫耳)之乙酸(4ml)、甲醇(1ml)及水(1.0ml)溶液經加熱至70℃達64小時。經64小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮以生成呈膠之不純的標的化合物(85.3mg)。令粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(47.6mg,53.8%)。Let N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl-3,5, 9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H- 1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)- 4,4-Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxy Heterotridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)-6-(pyridin-2-yldimethyl sulfide A solution of acetic acid (Ix-1) (94.5 mg, 0.0498 mmol) in acetic acid (4 ml), methanol (1 ml) and water (1.0 ml) was heated to 70 ° C for 64 hours. After 64 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure to give the title compound (85.3 mg) which was imp. The crude product was purified by reverse phase chromatography (using the following conditions) to yield the compound (47.6 mg, 53.8%).

純化條件：Purification conditions:

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC純化。管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：80.0% H2 O/20.0%乙腈線性至65% H2 O/35%乙腈經8.5分鐘至0% H2 O/100% MeCN經9.0分鐘，維持於0% H2 O/100%乙腈經9.0至10.0分鐘。流速：25ml/分鐘。生成呈膠之標的化合物(47.6mg)(滯留時間2.87，觀察之質量=890.4376)。The residue was dissolved in dimethyl hydrazine (1 mL) and purified by reverse phase HPLC. Column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); gradient: 80.0% H 2 O/20.0 % acetonitrile is linear to 65% H 2 O/35% acetonitrile over 8.5 minutes to 0% H 2 O/100% MeCN over 9.0 min, maintained at 0% H 2 O / 100% acetonitrile over 9.0 to 10.0 min. Flow rate: 25 ml/min. The compound (47.6 mg) was obtained as a gel (retention time 2.87, observed mass = 890.4376).

QC條件：QC conditions:

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至50% H2 O/50%乙腈經3.75分鐘，5% H2 O/95%乙腈經4.0分鐘，維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2mL/分鐘。滯留時間=2.87；觀察之質量=890.4376。方法C：3分鐘LRMS[1/2M=889]。1 H NMR(甲醇-d4 )δ：8.41(d,J=4.7Hz,1H),7.99(s,3H),7.84-7.91(m,2H),7.26(t,J=5.9Hz,1H),5.21(s,3H),4.58(t,J=5.0Hz,6H),4.56(s,6H),3.95(t,J=8.8Hz,6H),3.89(t,J=5.0Hz,6H),3.86-3.88(m,3H),3.74-3.78(m,9H),3.71(dd,J=9.4,4.1Hz,3H),3.54-3.67(m,42H),2.80(t,J=7.0Hz,2H),2.16(t,J=7.3Hz, 2H),1.99(s,9H),1.68(quin,J=7.3Hz,2H),1.50-1.57(m,2H),1.35-1.44(m,2H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile Linear to 50% H 2 O/50% acetonitrile over 3.75 minutes, 5% H 2 O / 95% acetonitrile over 4.0 min, maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 min. Flow rate: 2 mL/min. Residence time = 2.87; observed mass = 890.4376. Method C: 3 minutes LRMS [1/2 M = 889]. 1 H NMR (methanol-d 4 ) δ: 8.41 (d, J = 4.7 Hz, 1H), 7.99 (s, 3H), 7.84 - 7.91 (m, 2H), 7.26 (t, J = 5.9 Hz, 1H) , 5.21 (s, 3H), 4.58 (t, J = 5.0 Hz, 6H), 4.56 (s, 6H), 3.95 (t, J = 8.8 Hz, 6H), 3.89 (t, J = 5.0 Hz, 6H) , 3.86-3.88 (m, 3H), 3.74 - 3.78 (m, 9H), 3.71 (dd, J = 9.4, 4.1 Hz, 3H), 3.54-3.67 (m, 42H), 2.80 (t, J = 7.0 Hz) , 2H), 2.16 (t, J = 7.3 Hz, 2H), 1.99 (s, 9H), 1.68 (quin, J = 7.3 Hz, 2H), 1.50-1.57 (m, 2H), 1.35-1.44 (m, 2H).

N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-胺基丙氧基)甲基]-1H-1,2,3-***-1-基}-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺氫氯酸鹽(42)N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-() Ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(B Amidino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl }-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-aminopropoxy)methyl]-1H-1,2,3-triazole-1- }}-2,5,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-4-yl]B Guanamine hydrochloride (42)

令(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]- 2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺甲酸三級丁酯(l-w-1)(210mg,0.119毫莫耳)之乙酸(8.0ml)、甲醇(2.0ml)及水(2.0ml)溶液經隔夜加熱至70℃。經18小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯和甲醇稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮。令粗產物經二氯甲烷(10ml)和甲醇(4ml)稀釋並加入4.0M氯化氫之二噁烷(2.0ml,8毫莫耳)溶液。令反應混合物於室溫下經隔夜攪拌。經18小時後，令反應物於減壓下經濃縮。令粗產物經乙酸乙酯(1ml)稀釋並加入庚烷(10ml)且經減壓下濃縮。隨後將產物置於高真空下達18小時以生成呈固體之標的化合物(198.8mg,106%)。方法C：3分鐘LRMS[M+Na=1561]。1 H NMR(甲醇-d4 )δ：8.13-8.21(m,3H),5.22(s,3H),4.71(s,9H),4.65(d,J=4.7Hz,6H),3.92-4.00(m,12H),3.90(d,J=4.3Hz,3H),3.58-3.80(m,51H),2.02(s,9H)。Let (1,3-bis[(1-S1-[(1S,2R,6R,7R,8S)-7-(acetamido)-4,4-dimethyl-3,5,9, 11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1, 2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethinyl)-4, 4-Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxa-10- Trialkyl-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)carbamic acid tert-butyl butyl ester (1w-1) (210 mg, A solution of 0.119 mmol of acetic acid (8.0 ml), methanol (2.0 ml) and water (2.0 ml) was heated overnight to 70 °C. After 18 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and methanol and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure. The crude product was diluted with dichloromethane (10 mL) and methanol (4 mL) and EtOAc (EtOAc) The reaction mixture was allowed to stir overnight at room temperature. After 18 hours, the reaction was concentrated under reduced pressure. The crude product was diluted with EtOAc (EtOAc) (EtOAc) The product was then placed under high vacuum for 18 h to yield compound (198.8 mg, 106%) as a solid. Method C: 3 minutes LRMS [M+Na=1561]. 1 H NMR (methanol-d 4 ) δ: 8.13 - 8.21 (m, 3H), 5.22 (s, 3H), 4.71 (s, 9H), 4.65 (d, J = 4.7 Hz, 6H), 3.92-4.00 ( m, 12H), 3.90 (d, J = 4.3 Hz, 3H), 3.58-3.80 (m, 51H), 2.02 (s, 9H).

6-疊氮基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧 雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(43)6-azido-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-) 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 , 8-diox Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]methyl}propan-2-yl)hexylamine (43)

對N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-胺基丙氧基)甲基]-1H-1,2,3-***-1-基}-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺氫氯酸鹽(42)(25mg,0.016毫莫耳)之N,N-二甲基甲醯胺(0.5ml)溶液加入N,N-二異丙基乙胺(0.0111ml,0.0635毫莫耳)並經攪拌10分鐘且隨後加入至純1-[(6-疊氮基己 醯基)氧基]吡咯啶-2,5-二酮(參閱PCT國際申請案號2011034951,2011年3月24日；6.05mg,0.0238毫莫耳)並令反應物於室溫下經攪拌18小時。隨後令該反應物經加熱至60℃達32小時。經32小時後，令該反應物於減壓下經濃縮。令粗產物經二甲亞碸(1ml)稀釋並通過注射濾器且令粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(6.2mg,23%)。For N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-) (acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13 -yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-( Ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-aminopropoxy)methyl]-1H-1,2,3-triazole-1 -yl}-2,5,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-4-yl] A solution of acetamide hydrochloride (42) (25 mg, 0.016 mmol) in N,N-dimethylformamide (0.5 ml) was added N,N-diisopropylethylamine (0.0111 ml, 0.0635) Millions) and stirred for 10 minutes and then added to pure 1-[(6-azidohexyl)oxy]pyrrolidine-2,5-dione (See PCT International Application No. 2011034951, March 24, 2011; 6.05 mg, 0.0238 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was then allowed to warm to 60 ° C for 32 hours. After 32 hours, the reaction was concentrated under reduced pressure. The crude product was diluted with dimethyl sulfonium (1 ml) and purified by a syringe filter, and the crude product was purified by reverse phase chromatography (using the following conditions) to give a compound (6.2 mg, 23%).

純化條件Purification conditions

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC純化(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；90.0% H2 O/10.0%乙腈線性至70% H2 O/30%乙腈經10.5分鐘；70% H2 O/30%乙腈線性至0% H2 O/100% MeCN經0.5分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘。流速：25ml/分鐘。The residue was dissolved in dimethyl hydrazine (1 ml) and purified by reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05 % TFA acetonitrile solution (v/v); 90.0% H 2 O/10.0% acetonitrile linear to 70% H 2 O/30% acetonitrile over 10.5 minutes; 70% H 2 O/30% acetonitrile linear to 0% H 2 O / 100% MeCN over 0.5 min; maintained at 0% H 2 O / 100% acetonitrile over 11.0 to 12.0 minutes flow rate: 25ml / min.

QC條件QC condition

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.77分鐘；觀察之質量= 839.7097。方法C：3分鐘LRMS[M+1=1678]。1 H NMR(甲醇-d4 )δ：8.00(s,3H),5.21(s,3H),4.58(t,J=4.7Hz,6H),4.57(s,6H),3.95(t,J=10.0Hz,6H),3.85-3.92(m,9H),3.74-3.80(m,9H),3.71(dd,J=10.0,4.1Hz,3H),3.55-3.68(m,42H),3.25(t,J=6.5Hz,2H),2.19(t,J=7.3Hz,2H),1.99(s,9H),1.52-1.62(m,4H),1.33-1.41(m,2H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 minutes. Flow rate: 2 ml/min; residence time = 1.77 min; observed mass = 839.7097. Method C: 3 minutes LRMS [M+1 = 1678]. 1 H NMR (methanol-d 4 ) δ: 8.00 (s, 3H), 5.21. (s, 3H), 4.58 (t, J = 4.7 Hz, 6H), 4.57 (s, 6H), 3.95 (t, J = 10.0 Hz, 6H), 3.85-3.92 (m, 9H), 3.74-3.80 (m, 9H), 3.71 (dd, J = 10.0, 4.1 Hz, 3H), 3.55-3.68 (m, 42H), 3.25 (t , J = 6.5 Hz, 2H), 2.19 (t, J = 7.3 Hz, 2H), 1.99 (s, 9H), 1.52-1.62 (m, 4H), 1.33-1.41 (m, 2H).

N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)庚-6-烯醯胺(44)N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy Methyl}propan-2-yl)hept-6-eneamine (44)

對N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-胺基丙氧基)甲基]-1H-1,2,3-***-1-基}-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺氫氯酸鹽(42)(25mg,0.016毫莫耳)之N,N-二甲基甲醯胺(0.5ml)溶液加入N,N-二異丙基乙胺(0.0111ml,0.0635毫莫耳)並經攪拌10分鐘且隨後加入至純1-(庚-6-烯醯氧基)吡咯啶-2,5-二酮(參閱文獻Angewandte Chemie,International Edition,51(25),6144-6148,S6144/1-S6144/53,2012；5.36mg,0.0238毫莫耳)並令反應物於室溫下經攪拌18小時。隨後令該反應物經加熱至60℃達32小時。經32小時後，令該反應物於減壓下經濃縮。令粗產物經二甲亞碸(1ml)稀釋並通過注射濾器且令該粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(4.9mg,19%)。For N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-) (acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13 -yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-( Ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-aminopropoxy)methyl]-1H-1,2,3-triazole-1 -yl}-2,5,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-4-yl] A solution of acetamide hydrochloride (42) (25 mg, 0.016 mmol) in N,N-dimethylformamide (0.5 ml) was added N,N-diisopropylethylamine (0.0111 ml, 0.0635) Milligram) and stirred for 10 minutes and then added to pure 1-(hept-6-enyloxy)pyrrolidine-2,5-dione (See references Angewandte Chemie, International Edition, 51(25), 6144-6148, S6144/1-S6144/53, 2012; 5.36 mg, 0.0238 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was then allowed to warm to 60 ° C for 32 hours. After 32 hours, the reaction was concentrated under reduced pressure. The crude product was diluted with dimethyl sulfonium (1 ml) and passed through a syringe filter and the crude product was purified by reverse phase chromatography (using the following conditions) to yield the compound (4.9 mg, 19%).

純化條件：Purification conditions:

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC純化(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至55% H2 O/45%乙腈經10.5分鐘；55% H2 O/45%乙腈線性至0% H2 O/100% MeCN經0.5分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘。流速：25ml/分鐘。The residue was dissolved in dimethyl hydrazine (1 ml) and purified by reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05 % TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 55% H 2 O/45% acetonitrile over 10.5 minutes; 55% H 2 O/45% acetonitrile linear to 0% H 2 O / 100% MeCN over 0.5 min; maintained at 0% H 2 O / 100% acetonitrile over 11.0 to 12.0 minutes flow rate: 25ml / min.

QC條件：QC conditions:

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.81；觀察之質量=825.2381。方法C：3分鐘LRMS[M-1=1647]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),5.69-5.88(m,1H),5.21(s,3H),4.95(m,2H),4.51-4.63(m,12H),3.95(t,J=9.7Hz,6H),3.85-3.91(m,9H),3.74-3.81(m,9H),3.71(dd,J=9.4,4.1Hz,3H),3.54-3.68(m,42H),2.17(t,J=7.3Hz,2H),2.01-2.09(m,2H),1.99(s,9H),1.52-1.61(m,2H),1.39(quin,J=7.5Hz,2H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 minutes. Flow rate: 2 ml/min; residence time = 1.81; observed mass = 825.2381. Method C: 3 minutes LRMS [M-1 = 1647]. 1 H NMR (methanol -d 4) δ: 7.99 (s , 3H), 5.69-5.88 (m, 1H), 5.21 (s, 3H), 4.95 (m, 2H), 4.51-4.63 (m, 12H), 3.95 (t, J = 9.7 Hz, 6H), 3.85-3.91 (m, 9H), 3.74-3.81 (m, 9H), 3.71 (dd, J = 9.4, 4.1 Hz, 3H), 3.54-3.68 (m, 42H), 2.17 (t, J = 7.3 Hz, 2H), 2.01-2.09 (m, 2H), 1.99 (s, 9H), 1.52-1.61 (m, 2H), 1.39 (quin, J = 7.5 Hz, 2H) ).

N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙 環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)庚-6-炔醯胺(45)N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa double Cyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy Methyl}propan-2-yl)hept-6-ynylamine (45)

對N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-胺基丙氧基)甲基]-1H-1,2,3-***-1-基}-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺氫氯酸鹽(42)(25mg,0.016毫莫耳)之N,N-二甲基甲醯胺(0.5ml)溶液加入N,N-二異丙基乙胺(0.0111ml,0.0635毫莫耳)並經攪拌10分鐘且隨後加入至純1-(庚-6-炔醯氧 基)吡咯啶-2,5-二酮(參閱PCT國際申請案號2007056389,2007年5月18日；5.31mg,0.0238毫莫耳)並令反應物於室溫下經攪拌18小時。隨後令該反應物經加熱至60℃達32小時。經32小時後，令該反應物於減壓下經濃縮。令粗產物經二甲亞碸(1ml)稀釋並通過注射濾器且令該粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(5mg,19%)。For N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-) (acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13 -yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-( Ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-aminopropoxy)methyl]-1H-1,2,3-triazole-1 -yl}-2,5,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-4-yl] A solution of acetamide hydrochloride (42) (25 mg, 0.016 mmol) in N,N-dimethylformamide (0.5 ml) was added N,N-diisopropylethylamine (0.0111 ml, 0.0635) Milligram) and stirred for 10 minutes and then added to pure 1-(hept-6-alkynoxy)pyrrolidine-2,5-dione (See PCT International Application No. 2007056389, May 18, 2007; 5.31 mg, 0.0238 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was then allowed to warm to 60 ° C for 32 hours. After 32 hours, the reaction was concentrated under reduced pressure. The crude product was diluted with dimethyl sulfonium (1 ml) and passed through a syringe filter and the crude product was purified by reverse phase chromatography (using the following conditions) to give the compound (5 mg, 19%).

純化條件：Purification conditions:

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC純化(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至55% H2 O/45%乙腈經10.5分鐘；55% H2 O/45%乙腈線性至0% H2 O/100% MeCN經0.5分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘。流速：25ml/分鐘。The residue was dissolved in dimethyl hydrazine (1 ml) and purified by reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05 % TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 55% H 2 O/45% acetonitrile over 10.5 minutes; 55% H 2 O/45% acetonitrile linear to 0% H 2 O / 100% MeCN over 0.5 min; maintained at 0% H 2 O / 100% acetonitrile over 11.0 to 12.0 minutes flow rate: 25ml / min.

QC條件：QC conditions:

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.68；觀察之質量= 824.2237。方法C：3分鐘LRMS[1/2M=823]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),5.21(s,3H),4.59(t,J=5.0Hz,6H),4.56(s,6H),3.95(t,J=10.0Hz,6H),3.85-3.92(m,9H),3.74-3.79(m,9H),3.71(dd,J=10.0,4.1Hz,3H),3.54-3.67(m,41H),2.13-2.24(m,6H),1.99(s,9H),1.66(quin,J=7.5Hz,2H),1.50(quin,J=7.3Hz,2H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 minutes. Flow rate: 2 ml/min; residence time = 1.68; observed mass = 824.2237. Method C: 3 minutes LRMS [1/2 M = 823]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 5.21. (s, 3H), 4.59 (t, J = 5.0 Hz, 6H), 4.56 (s, 6H), 3.95 (t, J = 10.0 Hz, 6H), 3.85-3.92 (m, 9H), 3.74-3.79 (m, 9H), 3.71 (dd, J = 10.0, 4.1 Hz, 3H), 3.54-3.67 (m, 41H), 2.13-2.24 (m, 6H), 1.99 (s, 9H), 1.66 (quin, J = 7.5 Hz, 2H), 1.50 (quin, J = 7.3 Hz, 2H).

7-[(2,5-二側氧基吡咯啶-1-基)氧基]-7-側氧基庚酸乙酯(l-z-1)7-[(2,5-Bistoxypyrrolidin-1-yl)oxy]-7-oxoheptanoic acid ethyl ester (l-z-1)

對7-乙氧基-7-側氧基庚酸(448mg,2.38毫莫耳)之N,N-二甲基甲醯胺(6.0ml)溶液先後加入N-羥基琥珀醯亞胺(329mg,2.86毫莫耳)和N-(3-二甲基胺基丙基)-N’-乙基碳二醯亞胺氫氯化物(559mg,2.86毫莫耳)。令反應物於室溫下經攪拌72小時。經72小時後，令該反應物經水驟冷並經二氯甲烷萃取3次。令結合之有機層經飽和碳酸氫鈉溶液和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 40g管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成呈膠之標的化合物(426mg,63%)。方法C：1.5分鐘LRMS[M+Na=308]。1 H NMR(甲醇-d4 )δ：4.12(q,J=7.0Hz,2H),2.83(s,4H),2.64(t,J=7.2Hz,2H),2.33(t,J=7.2Hz,2H),1.74(quin,J=7.4Hz,2H), 1.58-1.68(m,2H),1.40-1.53(m,2H),1.24(t,J=7.0Hz,3H)。7-ethoxy-7-oxoheptanoic acid (448 mg, 2.38 mmol) of N,N-dimethylformamide (6.0 ml) was added N-hydroxysuccinimide (329 mg, 2.86 mmol) and N-(3-dimethyl Aminopropyl)-N'-ethylcarbodiimide hydrochloride (559 mg, 2.86 mmol). The reaction was allowed to stir at room temperature for 72 hours. After 72 hours, the reaction was quenched with water and extracted thrice with dichloromethane. The combined organic layers were washed with aq. sodium hydrogen sulfate and brine, dried over sodium sulfate The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) Method C: 1.5 minutes LRMS [M+Na=308]. 1 H NMR (methanol-d 4 ) δ: 4.12 (q, J = 7.0 Hz, 2H), 2.83 (s, 4H), 2.64 (t, J = 7.2 Hz, 2H), 2.33 (t, J = 7.2 Hz) , 2H), 1.74 (quin, J = 7.4 Hz, 2H), 1.58-1.68 (m, 2H), 1.40-1.53 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H).

7-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-7-側氧基庚酸(鈉鹽)(46)7-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-di Oxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]methyl}propan-2-yl)amino]-7-oxoheptanoic acid (sodium salt) (46)

對N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四 氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-胺基丙氧基)甲基]-1H-1,2,3-***-1-基}-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺氫氯酸鹽(42)(30.0mg,0.019毫莫耳)之N,N-二甲基甲醯胺(0.5ml)溶液加入N,N-二異丙基乙胺(0.0133ml,0.0762毫莫耳)並經攪拌10分鐘且隨後加入至純7-[(2,5-二側氧基吡咯啶-1-基)氧基]-7-側氧基庚酸乙酯(I-z-1)(7.4mg,0.026毫莫耳)並令反應物於室溫下經攪拌18小時。隨後令該反應物經加熱至60℃達32小時。經32小時後，令該反應物經冷卻至室溫並經減壓下濃縮。令粗產物經乙醇(1ml)和水(0.03ml)稀釋並隨後加入12.5M氫氧化鈉水溶液(0.015ml,0.190毫莫耳)。令反應物於室溫下經攪拌3小時。經3小時後，令該反應物於減壓下經濃縮。令粗產物經二甲亞碸(1ml)稀釋並通過注射濾器。令溶液經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(3.7mg,11%)。For N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-) (acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13 -yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-( Ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetra Oxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-aminopropoxy)methyl]-1H-1, 2,3-Triazol-1-yl}-2,5,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy-6,8-dioxabicyclo[3.2. 1] octyl-4-yl]acetamide hydrochloride (42) (30.0 mg, 0.019 mmol) of N,N-dimethylformamide (0.5 ml) solution was added to N,N-diiso Propylethylamine (0.0133 ml, 0.0762 mmol) and stirred for 10 minutes and then added to the pure 7-[(2,5-di-oxypyrrolidin-1-yl)oxy]-7-sideoxy Ethyl heptanoate (Iz-1) (7.4 mg, 0.026 mmol) was taken and stirred at room temperature for 18 h. The reaction was then allowed to warm to 60 ° C for 32 hours. After 32 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with ethanol (1 mL) and water (0.03 mL) and then 1 &lt The reaction was allowed to stir at room temperature for 3 hours. After 3 hours, the reaction was concentrated under reduced pressure. The crude product was diluted with dimethyl hydrazine (1 ml) and passed through a syringe filter. The solution was purified by reverse phase chromatography (using the following conditions) to yield compound (3.7 mg, 11%).

純化條件Purification conditions

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC純化(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；90.0% H2 O/10.0%乙腈線性至70% H2 O/30%乙腈經10.5分鐘；70% H2 O/30%乙腈線性至0% H2 O/100% MeCN經0.5分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘。流 速：25ml/分鐘。The residue was dissolved in dimethyl hydrazine (1 ml) and purified by reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05 % TFA acetonitrile solution (v/v); 90.0% H 2 O/10.0% acetonitrile linear to 70% H 2 O/30% acetonitrile over 10.5 minutes; 70% H 2 O/30% acetonitrile linear to 0% H 2 O / 100% MeCN over 0.5 min; maintained at 0% H 2 O / 100% acetonitrile over 11.0 to 12.0 minutes flow rate: 25ml / min.

QC條件QC condition

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.58分鐘；觀察之質量=839.7097。方法C：MassLynx\Acid_3.0Min.olp-LRMS[M+1=1681]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),5.21(s,3H),4.58(t,J=4.7Hz,6H),4.56(s,6H),3.95(t,J=9.7Hz,6H),3.89(dt,J=9.8,4.8Hz,9H),3.74-3.79(m,9H),3.71(dd,J=10.0,4.1Hz,3H),3.53-3.67(m,42H),2.25(t,J=7.3Hz,2H),2.17(t,J=7.3Hz,2H),1.99(s,9H),1.58(dquin,J=14.3,7.3Hz,4H),1.31-1.39(m,2H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 minutes. Flow rate: 2 ml/min; residence time = 1.58 minutes; observed mass = 839.7097. Method C: MassLynx\Acid_3.0 Min.olp-LRMS [M+1=1681]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 5.21. (s, 3H), 4.58 (t, J = 4.7 Hz, 6H), 4.56 (s, 6H), 3.95 (t, J = 9.7 Hz, 6H), 3.89 (dt, J = 9.8, 4.8 Hz, 9H), 3.74 - 3.79 (m, 9H), 3.71 (dd, J = 10.0, 4.1 Hz, 3H), 3.53-3.67 (m, 42H) ), 2.25 (t, J = 7.3 Hz, 2H), 2.17 (t, J = 7.3 Hz, 2H), 1.99 (s, 9H), 1.58 (dquin, J = 14.3, 7.3 Hz, 4H), 1.31-1.39 (m, 2H).

{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸苄酯(47){6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8- Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl )methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-di Oxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Benzyl methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}carbamic acid benzyl ester (47)

令{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸苄酯(l-y-1)(308mg,0.162毫莫耳)之乙酸(6ml)、甲醇(1.5ml)及水(1.5ml)溶液經加熱至70℃達64小時。經64小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮以生成標的化合物(286mg，無，99%)。方法C：1.5分鐘LRMS[M+1=1787]。1 H NMR(甲醇-d4 )δ：7.98(s,3H),7.19-7.43(m,5H),5.21(s,3H),5.06(s,2H),4.50-4.66(m,12H),3.95(dd,J=9.6,5.7Hz,6H),3.86-3.91(m, 9H),3.74-3.78(m,9H),3.71(dd,J=10.0,4.1Hz,3H),3.54-3.67(m,42H),3.03-3.12(m,2H),2.11-2.24(m,2H),1.98(s,9H),1.51-1.63(m,2H),1.43-1.51(m,2H),1.33(d,J=6.6Hz,2H)。Let {6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamido)-4,4-dimethyl-3, 5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}- 1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylammonium) )-4,4-Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11- Tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl A solution of benzyl carbamate (ly-1) (308 mg, 0.162 mmol) in acetic acid (6 ml), methanol (1.5 ml) and water (1.5 ml) was heated to 70 ° C for 64 hours. After 64 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure to give the title compound (286mg, Method C: 1.5 minutes LRMS [M+1 = 1787]. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 7.19-7.43 (m, 5H), 5.21. (s, 3H), 5.06 (s, 2H), 4.50-4.66 (m, 12H), 3.95 (dd, J=9.6, 5.7 Hz, 6H), 3.86-3.91 (m, 9H), 3.74-3.78 (m, 9H), 3.71 (dd, J = 10.0, 4.1 Hz, 3H), 3.54-3.67 ( m, 42H), 3.03-3.12 (m, 2H), 2.11-2.24 (m, 2H), 1.98 (s, 9H), 1.51-1.63 (m, 2H), 1.43-1.51 (m, 2H), 1.33 ( d, J = 6.6 Hz, 2H).

6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺乙酸鹽(48)6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 ,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole- 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]methyl}propan-2-yl)hexylamine acetate (48)

令{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1- [(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸苄酯(47)(640mg,0.358毫莫耳)溶解於甲醇(20.0ml)和乙酸(0.041ml,0.717毫莫耳)。令溶液隨後通過H立方體(使用10% Pd/C(小筒)；使用下述參數：溫度：50℃；流速：1ml/分鐘；壓力=全部H2 (1巴))。收集溶液並經減壓下濃縮以生成呈白色泡沫之標的化合物(572mg,93%)。方法C：3分鐘LRMS[M+1=1652]。1 H NMR(甲醇-d4 )δ：8.00(s,3H),5.21(s,3H),4.59(t,J=4.9Hz,6H),4.56(s,6H),3.95(d,J=9.8Hz,6H),3.85-3.92(m,9H),3.74-3.79(m,9H),3.69-3.74(m,3H),3.55-3.69(m,42H),2.91(t,J=7.6Hz,2H),2.20(t,J=7.2Hz,2H),1.99(s,9H),1.90(s,3H),1.52-1.68(m,4H),1.34-1.43(m,2H)。Let {6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8- Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl Benzyl methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl} benzyl carbamate (47) (640 mg, 0.358 mmol) dissolved in methanol (20.0 ml) and acetic acid ( 0.041 ml, 0.717 mmol. The solution was then passed through an H cube (using 10% Pd/C (small cartridge); the following parameters were used: temperature: 50 ° C; flow rate: 1 ml/min; pressure = all H 2 (1 bar)). The solution was collected and concentrated under reduced pressure to give compound (yield: 572 mg, 93%). Method C: 3 minutes LRMS [M+1 = 1652]. 1 H NMR (methanol-d 4 ) δ: 8.00 (s, 3H), 5.21. (s, 3H), 4.59 (t, J = 4.9 Hz, 6H), 4.56 (s, 6H), 3.95 (d, J = 9.8 Hz, 6H), 3.85-3.92 (m, 9H), 3.74-3.79 (m, 9H), 3.69-3.74 (m, 3H), 3.55-3.69 (m, 42H), 2.91 (t, J = 7.6 Hz) , 2H), 2.20 (t, J = 7.2 Hz, 2H), 1.99 (s, 9H), 1.90 (s, 3H), 1.52-1.68 (m, 4H), 1.34-1.43 (m, 2H).

N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己醯胺(49)N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]methyl}propan-2-yl)amino]-6-oxooxyhexyl}-6-(2,5-di- oxo-2,5-dihydro-1H-pyrrole- 1-yl) hexylamine (49)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(48)(60mg,0.036毫莫耳)之N,N-二甲基甲醯胺(0.5ml)和四氫呋喃(0.5ml)溶液加入N,N-二異丙基乙胺(0.0253ml,0.145毫莫耳)和1-{6-[(2,5-二側氧基吡咯啶-1-基)氧基]-6-側氧基己基}-1H-吡咯-2,5-二酮(12.3mg,0.040毫莫耳)並於室溫下經攪拌16小時。經16小時後，令反應物於減壓下經濃縮。令粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(15.4mg,23%)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-) 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 ,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole- 4-yl)methoxy]methyl}propan-2-yl)hexylamine (48) (60 mg, 0.036 mmol) of N,N-dimethylformamide (0.5 ml) and tetrahydrofuran (0.5 M) solution was added N,N-diisopropylethylamine (0.0253 ml, 0.145 mmol) and 1-{6-[(2,5-di-oxypyrrolidin-1-yl)oxy]- 6-oxo-oxyhexyl}-1H-pyrrole-2,5-dione (12.3 mg, 0.040 mmol) and stirred at room temperature for 16 hours. After 16 hours, the reaction was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (using the following conditions) to afford compound (15.4 mg, 23%).

純化條件Purification conditions

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC管柱(Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：80.0% H2 O/20.0%乙腈線性至75% H2 O/25%乙腈經10.5分鐘至0% H2 O/100% MeCN經11.0分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘；流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC column (Waters Sunfire C18 19×100, 5 u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA Acetonitrile solution (v/v); gradient: 80.0% H 2 O/20.0% acetonitrile linear to 75% H 2 O/25% acetonitrile over 10.5 minutes to 0% H 2 O/100% MeCN over 11.0 min; % H 2 O/100% acetonitrile was purified by 11.0 to 12.0 min; flow rate: 25 ml/min.

QC條件QC condition

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.69分鐘；觀察之質量=923.4907。方法C：3分鐘LRMS[M-1=1843]。1 H NMR(甲醇-d4 )δ：8.00(s,3H),6.80(s,2H),5.21(s,3H),4.59(t,J=5.0Hz,6H),4.56(s,6H),3.95(t,J=9.7Hz,6H),3.90(t,J=5.0Hz,6H),3.88(d,J=4.1Hz,3H),3.74-3.79(m,9H),3.71(dd,J=10.0,4.1Hz,3H),3.55-3.68(m,42H),3.48(t,J=7.0Hz,2H),3.12(t,J=7.0Hz,2H),2.11-2.23(m,4H),1.99(s,9H),1.53-1.66(m,6H),1.48(quin,J=7.2Hz,2H),1.24-1.36(m,4H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); gradient: 95.0% H 2 O/5.0 % acetonitrile was linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 min. Flow rate: 2 ml/min; residence time = 1.69 min; observed mass = 923.4907. Method C: 3 minutes LRMS [M-1 = 1843]. 1 H NMR (methanol-d 4 ) δ: 8.00 (s, 3H), 6.80 (s, 2H), 5.21. (s, 3H), 4.59 (t, J = 5.0 Hz, 6H), 4.56 (s, 6H) , 3.95 (t, J = 9.7 Hz, 6H), 3.90 (t, J = 5.0 Hz, 6H), 3.88 (d, J = 4.1 Hz, 3H), 3.74 - 3.79 (m, 9H), 3.71 (dd, J = 10.0, 4.1 Hz, 3H), 3.55-3.68 (m, 42H), 3.48 (t, J = 7.0 Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H), 2.11-2.23 (m, 4H) ), 1.99 (s, 9H), 1.53-1.66 (m, 6H), 1.48 (quin, J = 7.2 Hz, 2H), 1.24-1.36 (m, 4H).

N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-[(溴乙醯基)胺基]己醯胺(50)N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-6-[(bromoethenyl)amino]hexylamine (50)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(48)(60mg,0.036毫莫耳)之N,N-二甲基甲醯胺(0.5ml)和四氫呋喃(0.5ml)溶液加入N,N-二異丙基乙胺(0.0253ml,0.145毫莫耳) 和6-[(溴乙醯基)胺基]己酸五氟苯酯(參閱文獻Chemistry-A European Journal,14(16),4939-4947,2008；16.7mg,0.0400毫莫耳)並於室溫下經攪拌16小時。經16小時後，令反應物於減壓下經濃縮。令該粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(4.4mg,6.4%)。觀察之質量：944.1543。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-) 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 ,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole- 4-yl)methoxy]methyl}propan-2-yl)hexylamine (48) (60 mg, 0.036 mmol) of N,N-dimethylformamide (0.5 ml) and tetrahydrofuran (0.5 M)) solution of N,N-diisopropylethylamine (0.0253 ml, 0.145 mmol) and 5-[(bromoethionyl)amino]pentacroic acid pentafluorophenyl ester (See the literature Chemistry-A European Journal, 14 (16), 4939-4947, 2008; 16.7 mg, 0.0400 mmol) and stirred at room temperature for 16 hours. After 16 hours, the reaction was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (using the following conditions) to yield compound (4.4 mg, 6.4%). Quality of observation: 944.1543.

純化條件Purification conditions

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：80.0% H2 O/20.0%乙腈線性至75% H2 O/25%乙腈經10.5分鐘至0% H2 O/100% MeCN經11.0分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘；流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05%) TFA acetonitrile solution (v/v); gradient: 80.0% H 2 O/20.0% acetonitrile linear to 75% H 2 O/25% acetonitrile over 10.5 minutes to 0% H 2 O/100% MeCN over 11.0 min; 0% H 2 O/100% acetonitrile was purified by 11.0 to 12.0 min; flow rate: 25 ml/min.

QC條件QC condition

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.64分鐘；觀察之質 量=944.1543。方法C：3分鐘LRMS[M+1=1886]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),5.21(s,3H),4.57-4.62(m,6H),4.56(s,6H),3.92-3.98(m,6H),3.83-3.91(m,10H),3.80(s,2H),3.69-3.79(m,12H),3.54-3.68(m,43H),3.13(t,J=6.7Hz,2H),2.18(d,J=6.5Hz,4H),1.98(s,9H),1.59-1.67(m,2H),1.51-1.59(m,4H),1.48(br.s.,2H),1.27-1.41(m,4H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); gradient: 95.0% H 2 O/5.0 % acetonitrile was linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 min. Flow rate: 2 ml/min; residence time = 1.64 minutes; observed mass = 944.1543. Method C: 3 minutes LRMS [M+1 = 1886]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 5.21 (s, 3H), 4.57-4.62 (m, 6H), 4.56 (s, 6H), 3.92-3.98 (m, 6H), 3.83-3.91 (m, 10H), 3.80 (s, 2H), 3.69-3.79 (m, 12H), 3.54-3.68 (m, 43H), 3.13 (t, J = 6.7 Hz, 2H), 2.18 (d, J=6.5 Hz, 4H), 1.98 (s, 9H), 1.59-1.67 (m, 2H), 1.51-1.59 (m, 4H), 1.48 (br.s., 2H), 1.27-1.41 (m, 4H) ).

{(1S)-1-環戊基-2-[(2,5-二側氧基吡咯啶-1-基)氧基]-2-側氧基乙基}胺甲酸9H-茀-9-基甲酯(l-aa-1){(1S)-1-cyclopentyl-2-[(2,5-di-oxypyrrolidin-1-yl)oxy]-2-oxoethyl}aminecarboxylic acid 9H-indole-9- Methyl ester (l-aa-1)

於5至10℃下將N,N’-二環己基碳二醯亞胺(247mg,1.2毫莫耳)分批加入至(2S)-環戊基{[(9H-茀-9-基甲氧基)羰基]胺基}乙醇酸(380mg,1.04毫莫耳)和N-羥基琥珀醯亞胺(137.6mg,1.2毫莫耳)之乾四氫呋喃(40ml)溶液。經加入完成後，令混合物於室溫下經隔夜攪拌。令混合物經冷卻至-20℃並隨後經過濾以除去副產物。令濾餅經冰冷四氫呋喃沖洗並令濾液經濃縮至乾燥狀態且經閃爍管柱(經石油醚：乙酸乙酯100：10至100：50洗提)純化以生成標的化合物(380mg,79%)。N,N'-Dicyclohexylcarbodiimide (247 mg, 1.2 mmol) was added in portions to (2S)-cyclopentyl{[(9H-茀-9-yl) at 5 to 10 °C Oxy)carbonyl]amino}glycolic acid (380 mg, 1.04 mmol) and a solution of N-hydroxysuccinimide (137.6 mg, 1.2 mmol) in dry tetrahydrofuran (40 mL). After the addition was completed, the mixture was stirred overnight at room temperature. The mixture was allowed to cool to -20 ° C and then filtered to remove by-products. The filter cake was rinsed with ice-cooled THF (EtOAc) EtOAc (EtOAc:EtOAc)

N~5~-胺甲醯基-N~2~-[(2S)-2-環戊基-2-{[(9H-茀-9-基甲氧基)羰基]胺基}乙醯基]-L-鳥胺酸(l-ab-1)N~5~-Aminomercapto-N~2~-[(2S)-2-cyclopentyl-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethyl) ]-L-ornithine (l-ab-1)

於0℃下對(2S)-2-胺基-5-(胺甲醯基胺基)戊酸(151mg,0.86毫莫耳)和碳酸氫鈉(72.5mg,0.86毫莫耳)之水(15ml)溶液加入四氫呋喃(10ml)。對所生成之混合物於氮氣下逐滴加入{(1S)-1-環戊基-2-[(2,5-二側氧基吡咯啶-1-基)氧基]-2-側氧基乙基}胺甲酸9H-茀-9-基甲酯(l-aa-1)(380mg,0.82毫莫耳)之1,2-二甲氧基乙烷(15ml)溶液。經加入後，令混合物於室溫下經隔夜攪拌。令反應混合物經甲基三級丁基醚(50ml)沖洗4次。丟棄有機相並令水層經氫氯酸水溶液(1M)酸化至pH=3至4。令溶液經氯仿/異丙醇(4：1)(50ml)萃取6次。令結合之有機層置於硫酸鈉上乾燥並經濃縮至乾燥狀態以生成呈白色固體之標的化合物(403mg,93.7%)。(2S)-2-Amino-5-(aminocarbamimidino)pentanoic acid (151 mg, 0.86 mmol) and sodium bicarbonate (72.5 mg, 0.86 mmol) at 0 °C 15 ml) solution was added to tetrahydrofuran (10 ml). The resulting mixture was added dropwise {(1S)-1-cyclopentyl-2-[(2,5-di-oxypyrrolidin-1-yl)oxy]-2-oxooxy group under nitrogen. A solution of ethylH-carbamic acid 9H-fluoren-9-ylmethyl ester (1-alpha-1) (380 mg, 0.82 mmol) in 1,2-dimethoxyethane (15 mL). After the addition, the mixture was stirred overnight at room temperature. The reaction mixture was washed 4 times with methyl tri-butyl ether (50 mL). The organic phase was discarded and the aqueous layer was acidified to pH = 3 to 4 with aqueous hydrochloric acid (1M). The solution was extracted 6 times with chloroform/isopropanol (4:1) (50 ml). The combined organic layers were dried over sodium sulphate and concentrated to dryness to afford compound ( 403 g, 93.

[(1S)-2-{[(2S)-5-(胺甲醯基胺基)-1-{[4-(羥基甲基)苯基]胺基}-1-側氧基戊-2-基]胺基}-1-環戊基-2-側氧基乙基]胺甲酸9H-茀-9-基甲酯(l-ac-1)[(1S)-2-{[(2S)-5-(Aminocarboxamido)-1-{[4-(hydroxymethyl)phenyl]amino}-1-pentyloxypentane-2 -yl]amino}-1-cyclopentyl-2-oxoethyl]aminecarboxylic acid 9H-fluoren-9-ylmethyl ester (l-ac-1)

對N~5~-胺甲醯基-N~2~-[(2S)-2-環戊基-2-{[(9H-茀-9-基甲氧基)羰基]胺基}乙醯基]-L-鳥胺酸(l-ab-1)(500mg,0.95毫莫耳)和4-胺基苄醇(470mg,3.82毫莫耳)之二氯甲烷/甲醇(30ml/15ml)溶液加入N-乙氧羰基-2-乙氧基-1,2-二氫喹啉(708mg,2.86毫莫耳)。隨後令反應混合物於室溫和黑暗下經隔夜攪拌。次晨，令反應物於減壓下經濃縮並令殘餘物經甲基三級丁基醚(100ml×3)沖洗。隨後令濾餅經製備性HPLC(參閱下述條件)純化以生成呈黃色固體之標的化合物(31mg,5.1%)。1H NMR(400MHz,DMSO)：δ 9.95(s,1H),8.09(d,1H),7.90-7.88(d,2H),7.73-7.71(t,2H),7.55-7.53(t,2H),7.41(t,2H),7.34-7.30(t,2H),7.24-7.22(d,2H),5.96(t,1H),5.39(s,2H),5.11-5.08(t,1H),4.44-4.42(d,3H),4.32-4.23(m,3H),3.96-3.92(t,1H),3.01-3.00(m,3H),2.15-2.13(m,1H),1.66-1.24(m,12H)；m/z C35H41N5O6：628.4(M+H)+；滯留時間：4.213分鐘。For N~5~-aminocarboxamyl-N~2~-[(2S)-2-cyclopentyl-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino} oxime a solution of methylene chloride/methanol (30 ml/15 ml) of 4-L-ornithine (l-ab-1) (500 mg, 0.95 mmol) and 4-aminobenzyl alcohol (470 mg, 3.82 mmol) N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (708 mg, 2.86 mmol) was added. The reaction mixture was then stirred overnight at room temperature and in the dark. The next morning, the reaction was concentrated under reduced pressure and the residue was washed with ethyl tri-butyl ether (100ml×3). The filter cake was then purified by preparative HPLC (see conditions below) to yield the title compound (31 mg, 5.1%). 1H NMR (400MHz, DMSO): δ 9.95 (s, 1H), 8.09 (d, 1H), 7.90-7.88 (d, 2H), 7.73-7.71 (t, 2H), 7.55-7.53 (t, 2H), 7.41(t,2H),7.34-7.30(t,2H),7.24-7.22(d,2H),5.96(t,1H),5.39(s,2H),5.11-5.08(t,1H),4.44- 4.42 (d, 3H), 4.32-4.23 (m, 3H), 3.96-3.92 (t, 1H), 3.01-3.00 (m, 3H), 2.15-2.13 (m, 1H), 1.66-1.24 (m, 12H) m/z C35H41N5O6: 628.4 (M+H)+; retention time: 4.213 minutes.

純化條件：Purification conditions:

管柱：DIKMA Diamonsil(2)C18 200×20mm,5um；移動相：30%乙腈之水溶液(0.1% TFA)至50%乙腈之水溶 液(0.1% TFA)；波長=220nm；進行濃縮且經冷凍乾燥。Column: DIKMA Diamonsil (2) C18 200 × 20mm, 5um; mobile phase: 30% acetonitrile aqueous solution (0.1% TFA) to 50% acetonitrile water soluble Liquid (0.1% TFA); wavelength = 220 nm; concentrated and lyophilized.

QC條件：QC conditions:

管柱：Ultimate XB-C18,3×50mm,3um；滯留時間：4.33分鐘；移動相：A)水(TFA(2.7ml)之水(4L)溶液)；B)乙腈(TFA(2.5ml)之乙腈(4L)溶液)洗提梯度1%至100%；波長：220nm；ee值：100%。管柱：Chiralcel OD-3 50×4.6mm I.D.,3um；滯留時間：1.923分鐘；移動相：乙醇(0.05% DEA)之CO2 溶液5%至40%；流速：2.5ml/分鐘；波長：254nm；ee值=100%。管柱：AD-350×4.6mm I.D.,3um；滯留時間：1.981分鐘；移動相：乙醇(0.05% DEA)之CO2 溶液5%至40%；流速：2.5ml/分鐘；波長：220nm。Column: Ultimate XB-C18, 3 x 50 mm, 3 um; residence time: 4.33 minutes; mobile phase: A) water (TFA (2.7 ml) in water (4 L) solution); B) acetonitrile (TFA (2.5 ml) Acetonitrile (4 L) solution) elution gradient 1% to 100%; wavelength: 220 nm; ee value: 100%. Column: Chiralcel OD-3 50×4.6mm ID, 3um; residence time: 1.923 minutes; mobile phase: ethanol (0.05% DEA) CO 2 solution 5% to 40%; flow rate: 2.5ml/min; wavelength: 254nm ; ee value = 100%. Column: AD-350×4.6 mm ID, 3 um; residence time: 1.981 minutes; mobile phase: ethanol (0.05% DEA) CO 2 solution 5% to 40%; flow rate: 2.5 ml/min; wavelength: 220 nm.

N~2~-[(2S)-2-胺基-2-環戊基乙醯基]-N~5~-胺甲醯基-N-[4-(羥基甲基)苯基]-L-鳥胺酸醯胺(l-ad-1)N~2~-[(2S)-2-Amino-2-cyclopentylethenyl]-N~5~-aminocarbazino-N-[4-(hydroxymethyl)phenyl]-L - guanamine amide (l-ad-1)

於5℃和氮氣下對[(1S)-2-{[(2S)-5-(胺甲醯基胺基)-1-{[4-(羥基甲基)苯基]胺基}-1-側氧基戊-2-基]胺基}-1-環戊基-2-側氧基乙基]胺甲酸9H-茀-9-基甲酯(l-ac-1)(500mg, 0.797毫莫耳)之N,N-二甲基甲醯胺(10ml)攪拌溶液逐滴加入哌啶(4ml)。令混合物於室溫下經攪拌1.5小時。令反應物經濃縮至乾燥狀態。令粗產物經二氯甲烷(20ml)沖洗並經過濾且令濾餅經真空乾燥以生成呈固體之標的化合物(300mg,93.1%)，其未經純化而用於下一個步驟。[(1S)-2-{[(2S)-5-(Aminomethylamino)-1-{[4-(hydroxymethyl)phenyl]amino}}-1 at 5 ° C under nitrogen -Phenoxy-2-enyl]amino}-1-cyclopentyl-2-oxoethyl]aminecarboxylic acid 9H-indol-9-ylmethyl ester (l-ac-1) (500 mg, A stirred solution of 0.797 mmol of N,N-dimethylformamide (10 ml) was added dropwise to piperidine (4 ml). The mixture was stirred at room temperature for 1.5 hours. The reaction was concentrated to dryness. The crude product was washed with EtOAc (EtOAc)EtOAc.

N-[(1S)-2-{[(2S)-5-(胺甲醯基胺基)-1-{[4-(羥基甲基)苯基]胺基}-1-側氧基戊-2-基]胺基}-1-環戊基-2-側氧基乙基]-6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己醯胺(l-ae-1)N-[(1S)-2-{[(2S)-5-(Aminomethylamino)-1-{[4-(hydroxymethyl)phenyl]amino}-1-oxide pentane -2-yl]amino}-1-cyclopentyl-2-yloxyethyl]-6-(2,5-di- oxo-2,5-dihydro-1H-pyrrol-1-yl Hexylamine (l-ae-1)

於3℃和氮氣下對N~2~-[(2S)-2-胺基-2-環戊基乙醯基]-N~5~-胺甲醯基-N-[4-(羥基甲基)苯基]-L-鳥胺酸醯胺(l-ad-1)(300mg,0.74毫莫耳)之N,N-二甲基甲醯胺(12ml)攪拌溶液加入1-{6-[(2,5-二側氧基吡咯啶-1-基)氧基]-6-側氧基己基}-1H-吡咯-2,5-二酮(272mg,0.889毫莫耳)。令混合物於室溫下經攪拌2小時。將反應物逐滴加入至甲基三級丁基醚(250ml)，於室溫下經攪拌20分鐘，經過濾且令濾餅經濃縮至乾燥狀態以生成呈固體之標的化合物(300mg,67.8%)，其未經純化而用於下一個步驟。N~2~-[(2S)-2-Amino-2-cyclopentylethenyl]-N~5~-aminecarbenyl-N-[4-(hydroxyl) at 3 ° C under nitrogen a solution of N,N-dimethylformamide (12 ml) in a stirred solution of phenyl]-L-orndomamine (l-ad-1) (300 mg, 0.74 mmol) was added to 1-{6- [(2,5-Di-oxypyrrolidin-1-yl)oxy]-6-oxooxyhexyl}-1H-pyrrole-2,5-dione (272 mg, 0.889 mmol). The mixture was stirred at room temperature for 2 hours. The reaction was added dropwise to methyl tri-tert-butyl ether (250 ml), stirred at room temperature for 20 min, filtered and filtered to dryness to dryness to afford compound (300 mg, 67. ), which was used in the next step without purification.

N~5~-胺甲醯基-N~2~-[(2S)-2-環戊基-2-{[6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己醯基]胺基}乙醯基]-N-[4- ({[(4-硝基苯氧基)羰基]氧基}甲基)苯基]-L-鳥胺酸醯胺(l-af-1)N~5~-Aminomercapto-N~2~-[(2S)-2-cyclopentyl-2-{[6-(2,5-di- oxo-2,5-dihydro-1H) -pyrrol-1-yl)hexyl]amino}ethyl}yl]-N-[4- ({[(4-Nitrophenoxy)carbonyl)oxy}methyl)phenyl]-L-ornoxamine (l-af-1)

於3℃和氮氣下對N-[(1S)-2-{[(2S)-5-(胺甲醯基胺基)-1-{[4-(羥基甲基)苯基]胺基}-1-側氧基戊-2-基]胺基}-1-環戊基-2-側氧基乙基]-6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己醯胺(l-ae-1)(300mg,0.740毫莫耳)之N,N-二甲基甲醯胺(12ml)攪拌溶液加入碳酸二(4-硝基苯酯)(900mg,2.96毫莫耳)和N,N-二異丙基乙胺(390mg,2.96毫莫耳)。令反應物於室溫下經隔夜攪拌。將該反應物逐滴加入至甲基三級丁基醚(60ml)，於室溫下經攪拌20分鐘，經過濾且令濾餅經甲基三級丁基醚(100ml)沖洗。令粗產物經真空乾燥至乾燥狀態。令粗產物經閃爍管柱(經二氯甲烷：甲醇=100：1至94：6洗提)純化以生成呈固體之標的化合物(50mg,17.7%)。1 H NMR(400MHz,DMSO)：δ10.09(br,1H),8.33(d,2H),8.13(d,1H),7.93(d,1H),7.67-7.41(m,6H),7.01(s,2H),5.98(br,1H),5.43(s,2H),5.25(s,2H),4.39(m,1H),4.23-4.19(m,1H),3.37(m,1H),3.03-2.96(m,2H),2.14-2.11(m,3H),1.70-1.19(m,19H)。LC-MS：m/z C37H45N7O11：764.3(M+H)+；滯留時間：0.823分鐘。N-[(1S)-2-{[(2S)-5-(Aminocarboxamido)-1-{[4-(hydroxymethyl)phenyl]amine) at 3 ° C under nitrogen -1-pivaloxypentan-2-yl]amino}-1-cyclopentyl-2-yloxyethyl]-6-(2,5-di-oxo-2,5-dihydro- 1H-pyrrol-1-yl)hexylamine (l-ae-1) (300 mg, 0.740 mmol) of N,N-dimethylformamide (12 ml) was added to a stirred solution of di-(4-nitro Phenyl ester) (900 mg, 2.96 mmol) and N,N-diisopropylethylamine (390 mg, 2.96 mmol). The reaction was allowed to stir overnight at room temperature. The reaction was added dropwise to methyl tri-tert-butyl ether (60 mL) and stirred at room temperature for 20 min. The crude product was dried under vacuum to dryness. The crude product was purified on a flash column (eluent eluting with dichloromethane:methanol = 100:1 to 94:6) to afford compound (50mg, 17.7%) as a solid. 1 H NMR (400MHz, DMSO) : δ10.09 (br, 1H), 8.33 (d, 2H), 8.13 (d, 1H), 7.93 (d, 1H), 7.67-7.41 (m, 6H), 7.01 ( s, 2H), 5.98 (br, 1H), 5.43 (s, 2H), 5.25 (s, 2H), 4.39 (m, 1H), 4.23-4.19 (m, 1H), 3.37 (m, 1H), 3.03 - 2.96 (m, 2H), 2.14 - 2.11 (m, 3H), 1.70-1.19 (m, 19H). LC-MS: m/z C37H45N7O11: 764.3 (M+H)+;

{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸4-{[(2R)-5-(胺甲醯基胺基)-2-{[(2R)-2-環戊基-2-{[6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己醯基]胺基}乙醯基]胺基}戊醯基]胺基}苄酯(51){6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8- Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl )methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-di Oxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}carbamic acid 4-{[(2R)-5-(aminocarboxamido)-2-{[( 2R)-2-cyclopentyl-2-{[6-(2,5-di- oxy-2,5-dihydro-1H-pyrrol-1-yl)hexyl]amino}ethenyl Amino}pentanyl]amino}benzyl ester (51)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(48)(45mg, 0.027毫莫耳)之N,N-二甲基甲醯胺(0.5ml)和四氫呋喃(0.3ml)溶液加入N,N-二異丙基乙胺(0.019ml,0.109毫莫耳)和N~5~-胺甲醯基-N~2~-[(2S)-2-環戊基-2-{[6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己醯基]胺基}乙醯基]-N-[4-({[(4-硝基苯氧基)羰基]氧基}甲基)苯基]-L-鳥胺酸醯胺(I-af-1)(20.8mg,0.0272毫莫耳)並於室溫下經攪拌18小時。經18小時後，取出樣品且UPLC顯示生成所欲之產物。令粗反應混合物於減壓下經濃縮。令所生成之粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(21.7mg,35%)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-) 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 ,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole- 4-yl)methoxy]methyl}propan-2-ylhexylamine (48) (45 mg, 0.027 mmol of N,N-dimethylformamide (0.5 ml) and tetrahydrofuran (0.3 ml) were added N,N-diisopropylethylamine (0.019 ml, 0.109 mmol) and N~ 5~-Aminomethanyl-N~2~-[(2S)-2-cyclopentyl-2-{[6-(2,5-di- oxo-2,5-dihydro-1H-pyrrole) -1-yl)hexyl]amino}ethyl}ethyl]-N-[4-({[(4-nitrophenoxy)carbonyl]oxy}methyl)phenyl]-L-andniline The acid amide (I-af-1) (20.8 mg, 0.0272 mmol) was stirred at room temperature for 18 hours. After 18 hours, the sample was removed and UPLC showed the desired product. The crude reaction mixture was concentrated under reduced pressure. The crude product thus obtained was purified by reverse phase chromatography (using the following conditions) to give the compound (21.7 mg, 35%).

純化條件：Purification conditions:

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：75.0% H2 O/25.0%乙腈線性至65% H2 O/35%乙腈經10.5分鐘至0% H2 O/100% MeCN經11.0分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘。流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05%) TFA acetonitrile solution (v/v); gradient: 75.0% H 2 O/25.0% acetonitrile linear to 65% H 2 O/35% acetonitrile over 10.5 minutes to 0% H 2 O/100% MeCN over 11.0 min; 0% H 2 O/100% acetonitrile was purified by 11.0 to 12.0 min. flow rate: 25 ml/min.

QC條件：QC conditions:

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經 4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.99分鐘；滯留時間=1.99分鐘；觀察之質量=1139.1254。方法C：1.5分鐘LRMS[1/2M=1138]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),7.57(d,J=8.2Hz,2H),7.30(d,J=8.2Hz,2H),6.79(s,2H),5.21(s,3H),5.01(s,2H),4.55-4.64(m,12H),4.51(dd,J=9.0,5.1Hz,1H),4.43(q,J=7.2Hz,1H),4.16(d,J=9.4Hz,1H),3.95(d,J=9.8Hz,6H),3.85-3.91(m,9H),3.74-3.79(m,9H),3.71(dd,J=9.8,4.3Hz,3H),3.54-3.67(m,41H),3.47(t,J=7.0Hz,2H),3.16-3.26(m,1H),3.10-3.16(m,1H),3.07(t,J=6.8Hz,2H),2.24(q,J=7.7Hz,3H),2.16(t,J=7.4Hz,2H),1.99(s,9H),1.85-1.95(m,1H),1.42-1.84(m,16H),1.37(t,J=7.0Hz,2H),1.23-1.34(m,5H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 minutes. Flow rate: 2 ml/min; residence time = 1.99 minutes; residence time = 1.99 minutes; observed mass = 1139.1254. Method C: 1.5 minutes LRMS [1/2M = 1138]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 7.57 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 6.79 (s, 2H), 5.21. (s, 3H), 5.01 (s, 2H), 4.55-4.64 (m, 12H), 4.51 (dd, J = 9.0, 5.1 Hz, 1H), 4.43 (q, J = 7.2 Hz, 1H), 4.16 ( d, J=9.4 Hz, 1H), 3.95 (d, J=9.8 Hz, 6H), 3.85-3.91 (m, 9H), 3.74-3.79 (m, 9H), 3.71 (dd, J=9.8, 4.3 Hz) , 3H), 3.54-3.67 (m, 41H), 3.47 (t, J = 7.0 Hz, 2H), 3.16-3.26 (m, 1H), 3.10-3.16 (m, 1H), 3.07 (t, J = 6.8 Hz, 2H), 2.24 (q, J = 7.7 Hz, 3H), 2.16 (t, J = 7.4 Hz, 2H), 1.99 (s, 9H), 1.85-1.95 (m, 1H), 1.42-1.84 (m , 16H), 1.37 (t, J = 7.0 Hz, 2H), 1.23-1.34 (m, 5H).

N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-3,19-二側氧基-1-(吡啶-2-基二甲硫基)-7,10,13,16-四氧雜-4,20-二氮雜二十六烷-26-醯胺(52)N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy Methyl}propan-2-yl)-3,19-di- oxy-1-(pyridin-2-yldimethylthio)-7,10,13,16-tetraoxa-4,20 -diazahexadecane-26-nonylamine (52)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺乙酸鹽(48)(70.0mg,0.041毫莫耳)和N-{15-[(2,5-二側氧基吡咯啶-1-基)氧基]-15-側氧基-3,6,9,12-四氧雜十五烷-1-基}-3-(吡啶-2-基二甲硫基)丙醯胺(27.5mg,0.0491毫莫耳)之N,N-二甲基甲醯胺(0.6ml)和四氫呋喃(0.6ml)溶液加入N,N-二異丙基乙胺(0.0285ml,0.164毫莫耳)。令反應物於室溫下經攪拌18小時。經18小時後，令該反應物於減壓下經濃縮。令粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(47.7mg,56%)。方法C：3分鐘LRMS[1/3M+1=699]。1 H NMR(甲醇-d4 ) δ：8.47(d,J=4.7Hz,1H),8.01(s,3H),7.93(d,J=3.5Hz,2H),7.30-7.38(m,1H),5.21(s,3H),4.57-4.62(m,6H),4.57(s,6H),3.92-3.99(m,6H),3.89(dd,J=10.7,4.9Hz,9H),3.74-3.80(m,9H),3.72(dd,J=9.8,4.7Hz,6H),3.51-3.68(m,55H),3.35-3.41(m,2H),3.14(t,J=7.0Hz,2H),3.10(t,J=6.8Hz,2H),2.64(t,J=7.0Hz,2H),2.43(t,J=6.0Hz,2H),2.17(t,J=7.4Hz,2H),1.99(s,9H),1.52-1.61(m,2H),1.43-1.51(m,2H),1.27-1.38(m,2H)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-) 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 ,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole- 4-yl)methoxy]methyl}propan-2-ylhexylamine acetate (48) (70.0 mg, 0.041 mmol) and N-{15-[(2,5-di-oxyl) Pyrrolidin-1-yl)oxy]-15-tertiaryoxy-3,6,9,12-tetraoxapentadecan-1-yl}-3-(pyridin-2-yldimethylthio) Propylamine (27.5 mg, 0.0491 mmol) of N,N-dimethylformamide (0.6 ml) and tetrahydrofuran (0.6 ml) were added N,N-diisopropylethylamine (0.0285 ml, 0.164 mmol) ). The reaction was allowed to stir at room temperature for 18 hours. After 18 hours, the reaction was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (using conditions) to afford compound (47.7mg, 56%). Method C: 3 minutes LRMS [1/3M + 1 = 699]. 1 H NMR (methanol-d 4 ) δ: 8.47 (d, J = 4.7 Hz, 1H), 8.1 (s, 3H), 7.93 (d, J = 3.5 Hz, 2H), 7.30-7.38 (m, 1H) , 5.21 (s, 3H), 4.57-4.62 (m, 6H), 4.57 (s, 6H), 3.92-3.99 (m, 6H), 3.89 (dd, J = 10.7, 4.9 Hz, 9H), 3.74 - 3.80 (m, 9H), 3.72 (dd, J = 9.8, 4.7 Hz, 6H), 3.51-3.68 (m, 55H), 3.35-3.41 (m, 2H), 3.14 (t, J = 7.0 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H), 2.64 (t, J = 7.0 Hz, 2H), 2.43 (t, J = 6.0 Hz, 2H), 2.17 (t, J = 7.4 Hz, 2H), 1.99 ( s, 9H), 1.52-1.61 (m, 2H), 1.43-1.51 (m, 2H), 1.27-1.38 (m, 2H).

純化條件Purification conditions

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：80.0% H2 O/20.0%乙腈線性至70% H2 O/30%乙腈經8.5分鐘至0% H2 O/100% MeCN至9.0分鐘；維持於0% H2 O/100%乙腈經9.0至10.0分鐘；流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05%) TFA acetonitrile solution (v/v); gradient: 80.0% H 2 O/20.0% acetonitrile linear to 70% H 2 O/30% acetonitrile over 8.5 minutes to 0% H 2 O/100% MeCN to 9.0 minutes; 0% H 2 O/100% acetonitrile was purified over 9.0 to 10.0 min; flow rate: 25 ml/min.

QC條件QC condition

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.78分鐘；觀察之質 量=699.6404。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); gradient: 95.0% H 2 O/5.0 % acetonitrile was linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 min. Flow rate: 2 ml/min; residence time = 1.78 minutes; observed mass = 699.6404.

N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-3,31-二側氧基-1-(吡啶-2-基二甲硫基)-7,10,13,16,19,22,25,28-八氧雜-4,32-二氮雜三十八烷-38-醯胺(53)N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy Methyl}propan-2-yl)-3,31-di- oxy-1-(pyridin-2-yldimethylthio)-7,10,13,16,19,22,25,28 -octaoxa-4,32-diazatributocane-38-decylamine (53)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺乙酸鹽(48)(70.0mg,0.041毫莫耳)和N-{27-[(2,5-二側氧基吡咯啶-1-基)氧基]-27-側氧基-3,6,9,12,15,18,21,24-八氧雜二十 七烷-1-基}-3-(吡啶-2-基二甲硫基)丙醯胺 (30.1mg,0.041毫莫耳)之N,N-二甲基甲醯胺(0.6ml)和四氫呋喃(0.6ml)溶液加入N,N-二異丙基乙胺(0.0285ml,0.164毫莫耳)。令反應物於室溫下經攪拌18小時。經18小時後，令該反應物於減壓下經濃縮。令粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(59.2mg,64%)。方法C：3分鐘LRMS[1/3M=757]。1 H NMR(甲醇-d4 )δ：8.47(d,J=5.1Hz,1H),8.01(s,3H),7.92(d,J=3.5Hz,2H),7.30-7.39(m,1H),5.21(s,3H),4.57-4.62(m,6H),4.57(s,6H),3.92-3.99(m,6H),3.86-3.92(m,9H),3.77(s,9H),3.69-3.74(m,6H),3.50-3.68(m,73H),3.14(t,J=7.0Hz,2H),3.10(t,J=7.0Hz,2H),2.64(t,J=6.8Hz,2H),2.43(t,J=6.0Hz,2H),2.17(t,J=7.4Hz,2H),1.99(s,9H),1.53-1.63(m,2H),1.42-1.52(m,2H),1.32(dt,J=15.1,7.5Hz,2H)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-) 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 ,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole- 4-yl)methoxy]methyl}propan-2-ylhexylamine acetate (48) (70.0 mg, 0.041 mmol) and N-{27-[(2,5-di-oxyl) Pyrrolidin-1-yl)oxy]-27-tertiaryoxy-3,6,9,12,15,18,21,24-octaoxa-heptadecan-1-yl}-3-(pyridine -2-yldimethylthio)propanamide (30.1 mg, 0.041 mmol) of N,N-dimethylformamide (0.6 ml) and tetrahydrofuran (0.6 ml) were added N,N-diisopropylethylamine (0.0285 ml, 0.164 mmol) ). The reaction was allowed to stir at room temperature for 18 hours. After 18 hours, the reaction was concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (using the following conditions) to yield compound (59.2mg, 64%). Method C: 3 minutes LRMS [1/3M = 757]. 1 H NMR (methanol-d 4 ) δ: 8.47 (d, J = 5.1 Hz, 1H), 8.1 (s, 3H), 7.92 (d, J = 3.5 Hz, 2H), 7.30-7.39 (m, 1H) , 5.21 (s, 3H), 4.57-4.62 (m, 6H), 4.57 (s, 6H), 3.92-3.99 (m, 6H), 3.86-3.92 (m, 9H), 3.77 (s, 9H), 3.69 -3.74 (m, 6H), 3.50-3.68 (m, 73H), 3.14 (t, J = 7.0 Hz, 2H), 3.10 (t, J = 7.0 Hz, 2H), 2.64 (t, J = 6.8 Hz, 2H), 2.43 (t, J = 6.0 Hz, 2H), 2.17 (t, J = 7.4 Hz, 2H), 1.99 (s, 9H), 1.53-1.63 (m, 2H), 1.42-1.52 (m, 2H) ), 1.32 (dt, J = 15.1, 7.5 Hz, 2H).

純化條件Purification conditions

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：80.0% H2 O/20.0%乙腈線性至70% H2 O/30%乙腈經8.5分鐘至0% H2 O/100% MeCN至9.0分鐘；維持於0% H2 O/100%乙腈經9.0至10.0分鐘。流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05%) TFA acetonitrile solution (v/v); gradient: 80.0% H 2 O/20.0% acetonitrile linear to 70% H 2 O/30% acetonitrile over 8.5 minutes to 0% H 2 O/100% MeCN to 9.0 minutes; 0% H 2 O/100% acetonitrile was purified over 9.0 to 10.0 min. flow rate: 25 ml/min.

QC條件QC condition

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.85分鐘；觀察之質量=758.405。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); gradient: 95.0% H 2 O/5.0 % acetonitrile was linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 min. Flow rate: 2 ml/min; residence time = 1.85 min; observed mass = 758.405.

6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(l-ag-1)6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl-) 3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl }-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamidine) Amino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8, 11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine (l-ag- 1)

令{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸芾酯(l-y-1)(1200mg,0.63毫莫耳)溶解於甲醇(30ml)。令溶液隨後通過H立方體(使用10% Pd/C(小筒)；使用下述參數：溫度：50℃；流速：1ml/分鐘；壓力=全部H2 (1巴))。收集溶液。移除樣品且UPLC顯示起始物殘留。使用上述參數令反應物再次通過該H立方體。令所收集之溶液經減壓下濃縮以生成呈白色泡湯之標的化合物(1039mg,93%)。方法C：1.5分鐘LRMS[1/2M=886]。1 H NMR (甲醇-d4 )δ：7.99(s,3H),5.23(d,J=1.6Hz,3H),4.45-4.62(m,12H),4.29(d,J=5.9Hz,3H),4.16(t,J=6.4Hz,3H),3.87-3.98(m,12H),3.73-3.85(m,15H),3.54-3.70(m,36H),2.87(t,J=7.6Hz,2H),2.20(t,J=7.2Hz,2H),1.98(s,9H),1.53-1.69(m,4H),1.48(s,9H),1.34-1.41(m,2H),1.33(s,9H)。Let {6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamido)-4,4-dimethyl-3, 5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}- 1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylammonium) )-4,4-Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11- Tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl The oxime carbamate (ly-1) (1200 mg, 0.63 mmol) was dissolved in methanol (30 mL). The solution was then passed through an H cube (using 10% Pd/C (small cartridge); the following parameters were used: temperature: 50 ° C; flow rate: 1 ml/min; pressure = all H 2 (1 bar)). Collect the solution. The sample was removed and the UPLC showed the starting material residue. The above parameters were used to pass the reactants through the H cube again. The collected solution was concentrated under reduced pressure to give the title compound (1039 mg, 93%). Method C: 1.5 minutes LRMS [1/2 M = 886]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 5.23 (d, J = 1.6 Hz, 3H), 4.45 - 4.62 (m, 12H), 4.29 (d, J = 5.9 Hz, 3H) , 4.16 (t, J = 6.4 Hz, 3H), 3.87-3.98 (m, 12H), 3.73 - 3.85 (m, 15H), 3.54-3.70 (m, 36H), 2.87 (t, J = 7.6 Hz, 2H ), 2.20 (t, J = 7.2 Hz, 2H), 1.98 (s, 9H), 1.53-1.69 (m, 4H), 1.48 (s, 9H), 1.34-1.41 (m, 2H), 1.33 (s, 9H).

N-{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(吡啶-2-基二甲硫基)己醯胺(l-ag-2)N-{6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylammonium)-4,4-dimethyl-3) ,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl} -1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamide) -4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11 -tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-sideoxy Hexyl}-6-(pyridin-2-yldimethylthio)hexylamine (l-ag-2)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(l-ag-1)(105.0mg,0.0593毫莫耳)之N,N-二甲基甲醯胺(0.5ml)和四氫呋喃(0.5ml)溶液加入N,N-二異丙基乙胺(0.031ml,0.178毫莫耳)並經攪拌10分鐘且隨後加入至1-{[6-(吡啶-2-基二甲硫基)己醯基]氧基}吡咯啶-2,5-二酮(l-s-1)(25.2mg,0.0711毫莫耳)並隨後令反應物經加熱至室溫達16小時。經16小時後，令該反應物經水(15ml)和鹽水(5ml)稀釋並經二氯甲烷(20ml)萃取3次。令結合之有機層經水(20ml)和鹽水(20ml)沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成標的化合物(59.6mg,50%)。方法C：MassLynx\Acid_3.0Min.olp-LRMS[1/2M+1=1006]。1 H NMR(甲醇-d4 )δ：8.39(d,J=4.7Hz,1H),7.98(s,3H),7.83-7.87(m,1H),7.77-7.83(m,1H),7.21(t,J=5.9Hz,1H),5.23(d,J=1.6Hz,3H),4.50-4.64(m,12H),4.29(d,J=5.9Hz,3H),4.16(t,J=6.4Hz,3H),3.87-3.96(m,12H),3.84(d,J=7.8Hz,3H),3.71-3.79(m,15H),3.54-3.70(m,31H),3.18-3.28(m,2H),3.13(q,J=6.5Hz, 2H),2.82(t,J=7.2Hz,2H),2.12-2.23(m,4H),1.98(s,9H),1.71(quin,J=7.3Hz,2H),1.51-1.64(m,6H),1.44-1.51(m,11H),1.28-1.34(m,11H)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(B Amidino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine (l-ag -1) (105.0 mg, 0.0593 mmol) of N,N-dimethylformamide (0.5 ml) and tetrahydrofuran (0.5 ml) were added N,N-diisopropylethylamine (0.031 ml, 0.178) Milligram) and stirred for 10 minutes and then added to 1-{[6-(pyridin-2-yldimethylthio)hexanyl]oxy}pyrrolidine-2,5-dione (ls-1 (25.2 mg, 0.0711 mmol) and the reaction was then allowed to warm to room temperature for 16 h. After 16 hours, the reaction was diluted with water (15 mL) and brine The combined organic layers were washed with water (20 mL) and brine (20 mL). The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc. Method C: MassLynx\Acid_3.0 Min.olp-LRMS [1/2M+1=1006]. 1 H NMR (methanol-d 4 ) δ: 8.39 (d, J = 4.7 Hz, 1H), 7.98 (s, 3H), 7.83-7.87 (m, 1H), 7.77-7.83 (m, 1H), 7.21. t, J = 5.9 Hz, 1H), 5.23 (d, J = 1.6 Hz, 3H), 4.50 - 4.64 (m, 12H), 4.29 (d, J = 5.9 Hz, 3H), 4.16 (t, J = 6.4) Hz, 3H), 3.87-3.96 (m, 12H), 3.84 (d, J = 7.8 Hz, 3H), 3.71-3.79 (m, 15H), 3.54-3.70 (m, 31H), 3.18-3.28 (m, 2H), 3.13 (q, J = 6.5 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.12 - 2.23 (m, 4H), 1.98 (s, 9H), 1.71 (quin, J = 7.3) Hz, 2H), 1.51-1.64 (m, 6H), 1.44-1.51 (m, 11H), 1.28-1.34 (m, 11H).

N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(吡啶-2-基二甲硫基)己醯胺(54)N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-6-(pyridin-2-yldimethylthio)hexylamine (54)

令N-{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]- 2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(吡啶-2-基二甲硫基)己醯胺(l-ag-2)(59mg,0.029毫莫耳)之乙酸(4ml)、甲醇(1ml)及水(1ml)溶液經加熱至70℃達24小時。經24小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮以生成粗標的化合物(50.5mg,91%)。令粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(25.2mg,45%)。Let N-{6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl- 3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl }-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamidine) Amino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]- 2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino -6-Phenoxyhexyl}-6-(pyridin-2-yldimethylthio)hexylamine (l-ag-2) (59 mg, 0.029 mmol) of acetic acid (4 ml), methanol (1 ml And water (1 ml) solution was heated to 70 ° C for 24 hours. After 24 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure to yield crude compound (50.5mg, 91%). The crude product was purified by reverse phase chromatography (using the following conditions) to afford compound (25.2mg, 45%).

純化條件：Purification conditions:

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：80.0% H2 O/20.0%乙腈線性至70% H2 O/30%乙腈經10.5分鐘至0% H2 O/100% MeCN至11.0分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘；流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05%) TFA acetonitrile solution (v/v); gradient: 80.0% H 2 O/20.0% acetonitrile linear to 70% H 2 O/30% acetonitrile over 10.5 minutes to 0% H 2 O/100% MeCN to 11.0 min; 0% H 2 O/100% acetonitrile was purified by 11.0 to 12.0 min; flow rate: 25 ml/min.

QC條件：QC conditions:

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流 速：2ml/分鐘；滯留時間=1.96分鐘；觀察之質量=946.5137。方法C：MassLynx\Acid_3.0Min.olp-LRMS[1/2M+1=946]。1 H NMR(甲醇-d4 )δ：8.45(d,J=5.1Hz,1H),8.01(s,3H),7.94(d,J=3.1Hz,2H),7.29-7.36(m,1H),5.21(s,3H),4.57-4.62(m,6H),4.57(s,6H),3.92-4.00(m,6H),3.89(dd,J=10.7,4.9Hz,9H),3.74-3.80(m,9H),3.71(dd,J=10.1,4.3Hz,3H),3.53-3.68(m,42H),3.13(t,J=6.8Hz,2H),2.85(t,J=7.2Hz,2H),2.17(t,J=7.2Hz,4H),1.99(s,9H),1.71(quin,J=7.4Hz,2H),1.52-1.64(m,4H),1.45(td,J=15.0,7.8Hz,4H),1.26-1.37(m,2H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 minutes. Flow rate: 2 ml/min; residence time = 1.96 min; observed mass = 946.5137. Method C: MassLynx\Acid_3.0 Min.olp-LRMS [1/2M+1=946]. 1 H NMR (methanol-d 4 ) δ: 8.45 (d, J = 5.1 Hz, 1H), 8.1 (s, 3H), 7.94 (d, J = 3.1 Hz, 2H), 7.29-7.36 (m, 1H) , 5.21 (s, 3H), 4.57-4.62 (m, 6H), 4.57 (s, 6H), 3.92-4.00 (m, 6H), 3.89 (dd, J = 10.7, 4.9 Hz, 9H), 3.74 - 3.80 (m, 9H), 3.71 (dd, J = 10.1, 4.3 Hz, 3H), 3.53-3.68 (m, 42H), 3.13 (t, J = 6.8 Hz, 2H), 2.85 (t, J = 7.2 Hz, 2H), 2.17 (t, J = 7.2 Hz, 4H), 1.99 (s, 9H), 1.71 (quin, J = 7.4 Hz, 2H), 1.52-1.64 (m, 4H), 1.45 (td, J = 15.0) , 7.8 Hz, 4H), 1.26-1.37 (m, 2H).

{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸2-(吡啶-2-基二甲硫基)乙酯(l-ag-3){6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl-3,5 ,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H -1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino) -4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetra Oxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl} 2-(pyridin-2-yldimethylthio)ethyl carbamate (l-ag-3)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(l-ag-1)(61.4mg,0.0347毫莫耳)之N,N-二甲基甲醯胺(0.3ml)和四氫呋喃(0.3ml)溶液加入N,N-二異丙基乙胺(0.0241ml,0.139毫莫耳)和碳酸4-硝基苯酯2-(吡啶-2-基二甲硫基)乙酯(參閱文獻European Journal of Medicinal Chemistry,82,355-362,2014；18.0mg,0.051毫莫耳)並於室溫下經攪拌16小時。經16小時後，令反應混合物於減壓下經濃縮。令粗產物經CombiFlash Rf (RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(57.4mg，無，83%)。方法C：MassLynx\Acid_3.0Min.olp-LRMS[1/2M+1=993]。1 H NMR(甲醇-d4 )δ：8.40(d,J=4.3Hz,1H),7.98(s,3H),7.83-7.89(m,1H),7.75-7.83(m,1H),7.15-7.25(m,1H),5.22(d,J=1.2Hz,3H),4.51-4.64(m,12H),4.29(d,J=5.9Hz,3H),4.23(t,J=6.2Hz,2H),4.15(t,J=6.4Hz,3H),3.86-3.97(m,12H),3.83(d,J=7.8Hz,3H),3.72-3.79(m,12H),3.53-3.69(m,36H),3.05(t,J=5.7Hz,4H),2.17(t,J=7.0Hz,2H),1.98(s,9H),1.51-1.61(m,2H),1.48(s,11H),1.33(s,11H)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(B Amidino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine (l-ag -1) (61.4 mg, 0.0347 mmol) of N,N-dimethylformamide (0.3 ml) and tetrahydrofuran (0.3 ml) were added N,N-diisopropylethylamine (0.0241 ml, 0.139) Millol) and 4-nitrophenyl carbonate 2-(pyridin-2-yldimethylthio)ethyl ester (See European Journal of Medicinal Chemistry, 82, 355-362, 2014; 18.0 mg, 0.051 mmol) and stirred at room temperature for 16 hours. After 16 hours, the reaction mixture was concentrated under reduced pressure. The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) elute Method C: MassLynx\Acid_3.0 Min.olp-LRMS [1/2M+1=993]. 1 H NMR (methanol-d 4 ) δ: 8.40 (d, J = 4.3 Hz, 1H), 7.78 (s, 3H), 7.83-7.89 (m, 1H), 7.75-7.83 (m, 1H), 7.15- 7.25 (m, 1H), 5.22 (d, J = 1.2 Hz, 3H), 4.51-4.64 (m, 12H), 4.29 (d, J = 5.9 Hz, 3H), 4.23 (t, J = 6.2 Hz, 2H) ), 4.15 (t, J = 6.4 Hz, 3H), 3.86-3.97 (m, 12H), 3.83 (d, J = 7.8 Hz, 3H), 3.72-3.79 (m, 12H), 3.53-3.69 (m, 36H), 3.05 (t, J = 5.7 Hz, 4H), 2.17 (t, J = 7.0 Hz, 2H), 1.98 (s, 9H), 1.51-1.61 (m, 2H), 1.48 (s, 11H), 1.33 (s, 11H).

{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸2-(吡啶-2-基二甲硫基)乙酯(55){6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8- Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl )methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-di Oxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-carbamic acid 2-(pyridin-2-yldimethylthio)ethyl ester (55)

令{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸2-(吡啶-2-基二甲硫基)乙酯(l-ag-3)(57.4mg,0.0289毫莫耳)之乙酸(4.0ml)、甲醇(1.0ml)及水(1.0ml)溶液經加熱至70℃達24小時。經24小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令該粗產物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(29.8mg,55%)。Let {6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamido)-4,4-dimethyl-3, 5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}- 1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylammonium) )-4,4-Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11- Tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl } 2-(pyridin-2-yldimethylthio)ethyl amide (l-ag-3) (57.4 mg, 0.0289 mmol) of acetic acid (4.0 ml), methanol (1.0 ml) and water (1.0 Ml) The solution was heated to 70 ° C for 24 hours. After 24 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography (using the following conditions) to yield the compound (29.8 mg, 55%).

純化條件：Purification conditions:

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：80.0% H2 O/20.0%乙腈線性至70% H2 O/30%乙腈經10.5分鐘至0% H2 O/100% MeCN至11.0分鐘；維持於0% H2 O/100%乙腈經11.0至12.0分鐘；流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05%) TFA acetonitrile solution (v/v); gradient: 80.0% H 2 O/20.0% acetonitrile linear to 70% H 2 O/30% acetonitrile over 10.5 minutes to 0% H 2 O/100% MeCN to 11.0 min; 0% H 2 O/100% acetonitrile was purified by 11.0 to 12.0 min; flow rate: 25 ml/min.

QC條件：QC conditions:

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.91分鐘；觀察之質量=933.4313。方法C：MassLynx\Acid_3.0Min.olp-LRMS[1/2M+1=933]。1 H NMR(甲醇-d4 )δ：8.46(d,J=4.7Hz,1H),8.01(s,3H),7.86-7.97(m,2H),7.32(t,J=5.3Hz,1H),5.21(s,3H),4.55-4.62(m,12H),4.24(t,J=6.0Hz,2H),3.92-3.99(m,6H),3.85-3.92(m,9H),3.74-3.79(m,9H),3.71(dd,J=9.8,4.3Hz,3H),3.52-3.68(m,42H),2.99-3.15(m,4H),2.17(t,J=7.2Hz,2H),1.99(s,9H),1.56(quin,J=7.4Hz,2H),1.42-1.50(m,2H),1.24-1.38(m,2H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 minutes. Flow rate: 2 ml/min; residence time = 1.91 min; observed mass = 933.4313. Method C: MassLynx\Acid_3.0 Min.olp-LRMS [1/2M+1=933]. 1 H NMR (methanol-d 4 ) δ: 8.46 (d, J = 4.7 Hz, 1H), 8.1 (s, 3H), 7.86-7.97 (m, 2H), 7.32 (t, J = 5.3 Hz, 1H) , 5.21 (s, 3H), 4.55-4.62 (m, 12H), 4.24 (t, J = 6.0 Hz, 2H), 3.92-3.99 (m, 6H), 3.85-3.92 (m, 9H), 3.74-3.79 (m, 9H), 3.71 (dd, J = 9.8, 4.3 Hz, 3H), 3.52-3.68 (m, 42H), 2.99-3.15 (m, 4H), 2.17 (t, J = 7.2 Hz, 2H), 1.99 (s, 9H), 1.56 (quin, J = 7.4 Hz, 2H), 1.42-1.50 (m, 2H), 1.24-1.38 (m, 2H).

1-{[6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)己醯基]氧基}吡咯啶-2,5-二酮(l-ah-1)1-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexyl]oxy}pyrrolidine-2,5 -dione (l-ah-1)

令氯三(三苯膦)銠(I)Wilkinson氏觸媒(39.7mg,0.0429毫莫耳)之二氯甲烷(5.0ml)溶液經氮氣清洗10分鐘並隨後逐滴加入4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷(299mg,2.34毫莫耳，0.340ml)。令反應物於室溫下經攪拌10分鐘。令己-5-烯酸2,5-二側氧基吡咯啶-1-基酯(參閱文獻Journal of the American Chemical Society,132(35),12197-12199,2010；412mg,1.95毫莫耳)溶解於二氯甲烷(1.0ml)並逐滴加入。令反應物於室溫下經攪拌18小時。次晨，令該反應物經二氯甲烷稀釋且經水沖洗。令有機層置於硫酸鎂上乾燥並經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 24g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成粗標的化合物(366mg)。令該粗標的化合物經CombiFlash Rf(RediSep Gold 24g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成呈油之標的化合物(271.0mg，無，41.0%)。1 H NMR(甲醇-d4 )δ：2.83(s,4H),2.61(t,J=7.4Hz,2H),1.71(quin,J=7.1Hz,2H),1.38-1.50(m,4H),1.24(s,12H),0.75(t,J=6.8Hz,2H)。A solution of chlorotris(triphenylphosphine)ruthenium (I) Wilkinson's catalyst (39.7 mg, 0.0429 mmol) in dichloromethane (5.0 ml) was purged with nitrogen for 10 minutes and then added dropwise 4, 4, 5, 5-Tetramethyl-1,3,2-dioxaborolane (299 mg, 2.34 mmol, 0.340 ml). The reaction was allowed to stir at room temperature for 10 minutes. 2,5-di-oxypyrrolidin-1-yl hexa-5-enoate (See the literature Journal of the American Chemical Society, 132 (35), 12197-12199, 2010; 412 mg, 1.95 mmol) dissolved in dichloromethane (1.0 ml) and added dropwise. The reaction was allowed to stir at room temperature for 18 hours. The next morning, the reaction was diluted with dichloromethane and rinsed with water. The organic layer was dried over magnesium sulfate and filtered and evaporated. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc EtOAc The crude compound was purified on a CombiFlash Rf (RediSep Gold 24 g cartridge) eluting with 0 to 100% ethyl acetate / heptane gradient to yield the compound as oil (271.0 mg, s, 41.0%). 1 H NMR (methanol-d 4 ) δ: 2.83 (s, 4H), 2.61 (t, J = 7.4 Hz, 2H), 1.71 (quin, J = 7.1 Hz, 2H), 1.38-1.50 (m, 4H) , 1.24 (s, 12H), 0.75 (t, J = 6.8 Hz, 2H).

N-{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)己醯胺(l-ag-4)N-{6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylammonium)-4,4-dimethyl-3) ,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl} -1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamide) -4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11 -tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-sideoxy Hexyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexylamine (l-ag-4)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(l-ag-1)(200mg,0.113毫莫耳) 之N,N-二甲基甲醯胺(0.6ml)和四氫呋喃(0.6ml)溶液先後加入N,N-二異丙基乙胺(0.0786ml,0.451毫莫耳)和1-{[6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)己醯基]氧基}吡咯啶-2,5-二酮(l-ah-1)(57.4mg,0.169毫莫耳)並令反應物於室溫下經攪拌24小時。經24小時後，令該反應物於減壓下經濃縮。令粗產物經CombiFlash Rf(RediSep Gold 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(209.0mg，無，93%)。方法C：3分鐘LRMS[1/2M=998]。1 H NMR(甲醇-d4 )δ：7.98(s,3H),5.23(d,J=1.6Hz,3H),4.52-4.62(m,12H),4.29(d,J=5.9Hz,3H),4.16(t,J=6.4Hz,3H),3.87-3.97(m,12H),3.84(d,J=8.2Hz,3H),3.72-3.79(m,12H),3.54-3.69(m,36H),3.13(q,J=6.6Hz,2H),2.16(q,J=7.3Hz,4H),1.98(s,9H),1.52-1.66(m,4H),1.44-1.51(m,11H),1.35-1.43(m,2H),1.27-1.35(m,13H),1.18-1.25(m,12H),0.73(t,J=7.6Hz,2H)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(B Amidino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine (l-ag -1) (200 mg, 0.113 mmol) of N,N-dimethylformamide (0.6 ml) and tetrahydrofuran (0.6 ml) were added N,N-diisopropylethylamine (0.0786 ml, 0.451) Millol) and 1-{[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexyl]oxy}pyrrole Pyridine-2,5-dione (l-ah-1) (57.4 mg, 0.169 mmol) and the mixture was stirred at room temperature for 24 hours. After 24 hours, the reaction was concentrated under reduced pressure. The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) elute Method C: 3 minutes LRMS [1/2 M = 998]. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 5.23 (d, J = 1.6 Hz, 3H), 4.52-4.62 (m, 12H), 4.29 (d, J = 5.9 Hz, 3H) , 4.16 (t, J = 6.4 Hz, 3H), 3.87-3.97 (m, 12H), 3.84 (d, J = 8.2 Hz, 3H), 3.72-3.79 (m, 12H), 3.54-3.69 (m, 36H) ), 3.13 (q, J = 6.6 Hz, 2H), 2.16 (q, J = 7.3 Hz, 4H), 1.98 (s, 9H), 1.52-1.66 (m, 4H), 1.44-1.51 (m, 11H) , 1.35 - 1.43 (m, 2H), 1.27 - 1.35 (m, 13H), 1.18 - 1.25 (m, 12H), 0.73 (t, J = 7.6 Hz, 2H).

N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)己醯胺 (56)N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxo Heterocyclic pentaborane-2-yl) hexylamine (56)

令N-{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)己醯胺(l-ag-4)(104.0mg,0.0521毫莫耳)之乙酸(4ml)、甲醇(1ml)及水(1ml)溶液經加熱至70℃達24小時。經24小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮以生成粗標的化合物(112.0mg,115%)。令部分之粗標的化合物(52.7mg)經逆相層析純化以生成呈膠之標的化合物(18.2 mg,19%)。Let N-{6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl- 3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl }-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamidine) Amino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8, 11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-side oxygen Benzyl}-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanide (l-ag-4) (104.0 mg) A solution of 0.0521 mmol of acetic acid (4 ml), methanol (1 ml) and water (1 ml) was heated to 70 ° C for 24 hours. After 24 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was diluted with toluene and concentrated under reduced pressure to yield crude compound (112.0mg, 11%). Part of the crude standard compound (52.7 mg) was purified by reverse phase chromatography to give the compound as a gel (18.2) Mg, 19%).

純化條件Purification conditions

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：80.0% H2 O/20.0%乙腈線性至65% H2 O/35%乙腈經8.5分鐘至0% H2 O/100% MeCN至9.0分鐘；維持於0% H2 O/100%乙腈經9.0至10.0分鐘；流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05%) TFA acetonitrile solution (v/v); gradient: 80.0% H 2 O/20.0% acetonitrile linear to 65% H 2 O / 35% acetonitrile over 8.5 min to 0% H 2 O / 100% MeCN to 9.0 min; 0% H 2 O/100% acetonitrile was purified over 9.0 to 10.0 min; flow rate: 25 ml/min.

QC條件QC condition

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=2分鐘；觀察之質量=938.9628。1 H NMR(甲醇-d4 )δ：8.01(s,3H),5.21(s,3H),4.51-4.66(m,12H),3.95(dd,J=9.4,5.9Hz,6H),3.89(dd,J=11.7,4.7Hz,9H),3.74-3.81(m,9H),3.71(dd,J=9.8,4.3Hz,3H),3.52-3.68(m,42H),3.13(t,J=6.8Hz,2H),2.17(q,J=7.0Hz,4H),1.99(s,9H),1.53-1.66(m,4H),1.45-1.52(m,2H),1.36-1.44(m,2H),1.27-1.35(m,4H),1.23(s,12H),0.73(t,J=7.6Hz,2H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); gradient: 95.0% H 2 O/5.0 % acetonitrile was linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 min. Flow rate: 2 ml/min; residence time = 2 minutes; observed mass = 938.9628. 1 H NMR (methanol-d 4 ) δ: 8.01 (s, 3H), 5.21. (s, 3H), 4.51-4.66 (m, 12H), 3.95 (dd, J = 9.4, 5.9 Hz, 6H), 3.89 ( Dd, J = 11.7, 4.7 Hz, 9H), 3.74 - 3.81 (m, 9H), 3.71 (dd, J = 9.8, 4.3 Hz, 3H), 3.52-3.68 (m, 42H), 3.13 (t, J = 6.8 Hz, 2H), 2.17 (q, J = 7.0 Hz, 4H), 1.99 (s, 9H), 1.53-1.66 (m, 4H), 1.45-1.52 (m, 2H), 1.36-1.44 (m, 2H) ), 1.27 - 1.35 (m, 4H), 1.23 (s, 12H), 0.73 (t, J = 7.6 Hz, 2H).

7-[(1,3-二羥基丙-2-基)胺基]-7-側氧基庚酸乙酯(l-ai-1)7-[(1,3-Dihydroxypropan-2-yl)amino]-7-oxoheptanoheptanoic acid ethyl ester (l-ai-1)

對7-[(2,5-二側氧基吡咯啶-1-基)氧基]-7-側氧基庚酸乙酯(l-z-1)(228.0mg,0.799毫莫耳)之N,N-二甲基甲醯胺(1.0ml)溶液加入N,N-二異丙基乙胺(0.557ml,3.20毫莫耳)並經攪拌10分鐘且隨後加入2-胺基丙烷-1,3-二醇(72.8mg,0.799毫莫耳)並令反應物於室溫下經攪拌72小時。經72小時後，令該反應物經水稀釋並經二氯甲烷萃取3次。令結合之有機層經鹽水沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮以生成粗標的化合物(89.0mg，無，43%)。令水層經減壓下濃縮。令經濃縮之粗水層經甲醇(5ml)和二氯甲烷(10ml)稀釋。令混合物經傾析並與第一次萃取所得之粗標的化合物結合。令溶液經減壓下濃縮。令結合之粗產物經CombiFlash Rf(RediSep 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成標的化合物(183.0mg,88%)。方法C：3分鐘LRMS[M+1=262]。1 H NMR(甲醇-d4 )δ：4.11(q,J=7.2Hz,2H),3.83-3.99(m,1H),3.60(d,J=5.5Hz,4H),2.31(t,J=7.2Hz,2H),2.23(t,J=7.4Hz,2H),1.63(quin,J=7.5Hz,4H),1.30-1.45(m,2H),1.24(t,J=7.0Hz,3H)。N for 7-[(2,5-di-oxypyrrolidin-1-yl)oxy]-7-oxoheptanoic acid ethyl ester (lz-1) (228.0 mg, 0.799 mmol), A solution of N-dimethylformamide (1.0 ml) was added N,N-diisopropylethylamine (0.557 ml, 3.20 mmol) and stirred for 10 min and then 2-aminopropane-1,3 was added. -diol (72.8 mg, 0.799 mmol) and the reaction was stirred at room temperature for 72 h. After 72 hours, the reaction was diluted with water and extracted with dichloromethane three times. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered and evaporated. The aqueous layer was concentrated under reduced pressure. The concentrated aqueous layer was diluted with MeOH (5 mL) and dichloromethane (10 mL). The mixture was decanted and combined with the crude standard compound obtained by the first extraction. The solution was concentrated under reduced pressure. The combined crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) Method C: 3 minutes LRMS [M+1 = 262]. 1 H NMR (methanol-d 4 ) δ: 4.11 (q, J = 7.2 Hz, 2H), 3.83-3.99 (m, 1H), 3.60 (d, J = 5.5 Hz, 4H), 2.31 (t, J = 7.2 Hz, 2H), 2.23 (t, J = 7.4 Hz, 2H), 1.63 (quin, J = 7.5 Hz, 4H), 1.30 - 1.45 (m, 2H), 1.24 (t, J = 7.0 Hz, 3H) .

7-[(2,2-二甲基-1,3-二噁烷-5-基)胺基]-7-側氧基庚酸乙酯 (l-aj-1)7-[(2,2-Dimethyl-1,3-dioxan-5-yl)amino]-7-oxoheptanoheptanoate (l-aj-1)

對7-[(1,3-二羥基丙-2-基)胺基]-7-側氧基庚酸乙酯(l-ai-1)(180.0mg,0.689毫莫耳)之N,N-二甲基甲醯胺(2ml)溶液先後加入2,2-二甲氧基丙烷(0.53ml,4.13毫莫耳)和(1S)-(+)-10-樟腦磺酸(64.0mg,0.276毫莫耳)。令反應物經加熱至70℃達72小時。經72小時後，令該反應物經冷卻至室溫並分佈於水(20ml)和乙酸乙酯(10ml)中。令相層經萃取並分離相層。令該水層再經乙酸乙酯(10ml)沖洗2次。令結合之有機層經水和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮以生成粗標的化合物(94.0mg，無，45%)。N,N for 7-[(1,3-dihydroxypropan-2-yl)amino]-7-oxoheptanoheptanoate (l-ai-1) (180.0 mg, 0.689 mmol) -Dimethylformamide (2 ml) was added 2,2-dimethoxypropane (0.53 ml, 4.13 mmol) and (1S)-(+)-10-camphorsulfonic acid (64.0 mg, 0.276). Millions of ears). The reaction was allowed to warm to 70 ° C for 72 hours. After 72 hours, the reaction was cooled to EtOAc (EtOAc)EtOAc. The phase layer is extracted and the phase layer is separated. The aqueous layer was washed twice more with ethyl acetate (10 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate and evaporated.

7-[(2,2-二甲基-1,3-二噁烷-5-基)胺基]-7-側氧基庚酸(l-ak-1)7-[(2,2-Dimethyl-1,3-dioxan-5-yl)amino]-7-oxoheptanoic acid (l-ak-1)

對7-[(2,2-二甲基-1,3-二噁烷-5-基)胺基]-7-側氧基庚酸乙酯(l-aj-1)(94.0mg,0.31毫莫耳)之乙醇(5ml)溶液加入1.0M氫氧化鈉水溶液(1.5ml,1.5毫莫耳)並令反應物於室溫下經隔夜攪拌。次晨，令該反應物於減壓下經濃縮。令所生成之粗產物經1N氫氯酸(3.0ml)和乙酸乙酯稀釋。分離相層並令有機層再經乙酸乙酯萃取2次。令結合 之有機層經鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮以生成粗標的化合物(29.4mg，無，34%)。Ethyl 7-[(2,2-dimethyl-1,3-dioxan-5-yl)amino]-7-oxoheptanoate (l-aj-1) (94.0 mg, 0.31 A solution of the ethanol (5 ml) in EtOAc (1 mL) was then evaporated. The next morning, the reaction was concentrated under reduced pressure. The resulting crude product was diluted with 1N hydrochloric acid (3.0 mL) and ethyl acetate. The phase layer was separated and the organic layer was extracted twice with ethyl acetate. Combination The organic layer was washed with EtOAc (EtOAc m.

N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-N’-(1,3-二羥基丙-2-基)庚二醯胺(57)N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-N'-(1,3-dihydroxypropan-2-yl)heptanylamine (57)

對7-[(2,2-二甲基-1,3-二噁烷-5-基)胺基]-7-側氧基庚酸(l-ak-1)(18.8mg,0.0688毫莫耳)之N,N-二甲基甲醯胺(0.3ml)和四氫呋喃(0.3ml)溶液加入1-羥基苯並***(10.3mg,0.0762毫莫耳)和N-(3-二甲基胺基丙基)-N’-乙基碳二醯亞胺氫氯化物(14.9mg,0.0762毫莫耳)並令反應物於室溫下經攪拌1小時。將反應混合物加入至6-胺基-N-(1,3- 雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(l-ag-1)(75.0mg,0.042毫莫耳)並隨後加入N,N-二異丙基乙胺(0.0295ml,0.169毫莫耳)且令反應物於室溫下經攪拌16小時。經16小時後，令該反應物於減壓下經濃縮。令粗產物溶解於乙酸(4.0ml)、甲醇(1ml)及水(1.0ml)且經加熱至70℃達24小時。經24小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮以生成粗標的化合物(175.0mg,220%)。令該粗標的化合物經逆相層析(使用下述條件)純化以生成呈膠之標的化合物(10.9mg,14%)。For 7-[(2,2-dimethyl-1,3-dioxan-5-yl)amino]-7-oxoheptanoic acid (l-ak-1) (18.8 mg, 0.0688 mmol) A solution of N,N-dimethylformamide (0.3 ml) and tetrahydrofuran (0.3 ml) was added to 1-hydroxybenzotriazole (10.3 mg, 0.0762 mmol) and N-(3-dimethyl Aminopropyl)-N'-ethylcarbodiimide hydrochloride (14.9 mg, 0.0762 mmol) and the reaction was stirred at room temperature for 1 hour. Adding the reaction mixture to 6-amino-N-(1,3- Bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamido)-4,4-dimethyl-3,5,9,11-tetraoxa three Ring [6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(acetamido)-4,4-dimethyl- 3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13-yl }-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-ylhexylamine (l-ag-1) (75.0 mg, 0.042 mmol) Then N,N-diisopropylethylamine (0.0295 ml, 0.169 mmol) was added and the reaction was stirred at room temperature for 16 h. After 16 hours, the reaction was concentrated under reduced pressure. The crude product was dissolved in acetic acid (4.0 mL), methanol (1 mL) and water (1.0 mL) and warmed to 70 ° C for 24 hours. After 24 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure to yield crude compound (175.0mg, 220%). The crude standard compound was purified by reverse phase chromatography (using the following conditions) to yield the compound (10.9 mg, 14%).

純化條件：Purification conditions:

令殘餘物溶解於二甲亞碸(1ml)並經逆相HPLC(管柱：Waters Sunfire C18 19×100,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；梯度：85.0% H2 O/15.0%乙腈線性至75% H2 O/25%乙腈經8.5分鐘至0% H2 O/100% MeCN至9.0分鐘；維持於0% H2 O/100%乙腈經9.0至10.0分鐘；流速：25ml/分鐘)純化。The residue was dissolved in dimethyl hydrazine (1 ml) and subjected to reverse phase HPLC (column: Waters Sunfire C18 19×100, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05%) TFA acetonitrile solution (v/v); gradient: 85.0% H 2 O/15.0% acetonitrile linear to 75% H 2 O/25% acetonitrile over 8.5 minutes to 0% H 2 O/100% MeCN to 9.0 min; 0% H 2 O/100% acetonitrile was purified over 9.0 to 10.0 min; flow rate: 25 ml/min.

QC條件：QC conditions:

管柱：Waters Atlantis dC18 4.6×50,5u；移動相A：0.05% TFA水溶液(v/v)；移動相B：0.05% TFA乙腈溶液(v/v)；95.0% H2 O/5.0%乙腈線性至5% H2 O/95%乙腈經4.0分鐘；維持於5% H2 O/95%乙腈經4.0至5.0分鐘。流速：2ml/分鐘；滯留時間=1.53分鐘；觀察之質量=934.548。方法C：3分鐘LRMS[M+Na=1889]。1 H NMR(甲醇-d4 )δ：8.00(s,3H),5.21(s,3H),4.52-4.62(m,12H),3.95(t,J=9.4Hz,6H),3.85-3.91(m,9H),3.74-3.79(m,9H),3.71(dd,J=10.0,4.1Hz,3H),3.55-3.67(m,47H),3.12(t,J=6.7Hz,2H),2.22(t,J=7.3Hz,2H),2.17(t,J=7.3Hz,4H),1.98(s,9H),1.58-1.69(m,4H),1.51-1.57(m,2H),1.48(quin,J=7.2Hz,2H),1.26-1.40(m,4H)。Column: Waters Atlantis dC18 4.6×50, 5u; mobile phase A: 0.05% aqueous TFA solution (v/v); mobile phase B: 0.05% TFA acetonitrile solution (v/v); 95.0% H 2 O/5.0% acetonitrile linear to 5% H 2 O / 95% acetonitrile over 4.0 min; maintained at 5% H 2 O / 95% acetonitrile over 4.0 to 5.0 minutes. Flow rate: 2 ml/min; residence time = 1.53 minutes; observed mass = 934.548. Method C: 3 minutes LRMS [M+Na=1889]. 1 H NMR (methanol-d 4 ) δ: 8.00 (s, 3H), 5.21 (s, 3H), 4.52-4.62 (m, 12H), 3.95 (t, J = 9.4 Hz, 6H), 3.85-3.91 ( m, 9H), 3.74-3.79 (m, 9H), 3.71 (dd, J = 10.0, 4.1 Hz, 3H), 3.55-3.67 (m, 47H), 3.12 (t, J = 6.7 Hz, 2H), 2.22 (t, J = 7.3 Hz, 2H), 2.17 (t, J = 7.3 Hz, 4H), 1.98 (s, 9H), 1.58-1.69 (m, 4H), 1.51-1.57 (m, 2H), 1.48 ( Quin, J = 7.2 Hz, 2H), 1.26-1.40 (m, 4H).

6-疊氮基-N-{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺(l-ag-5)6-azido-N-{6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4 -Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxa Alkan-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)- 7-(acetamido)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2 ,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino] -6-oxooxyhexyl}hexylamine (l-ag-5)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(l-ag-1)(300mg,0.169毫莫耳)之N,N-二甲基甲醯胺(0.6ml)和四氫呋喃(0.6ml)溶液加入N,N-二異丙基乙胺(0.118ml,0.677毫莫耳)和1-[(6-疊氮基己醯基)氧基]吡咯啶-2,5-二酮(56.0mg,0.220毫莫耳)。令反應物於室溫下經攪拌24小時。經24小時後，令該反應物於減壓下經濃縮。使用CombiFlash Rf(RediSep Gold 24g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化粗反應混合物以生成呈膠之標的化合物(269mg,83%)。方法C：3分鐘LRMS[1/2M+1=956]。1 H NMR(甲醇-d4 ) δ：7.98(s,3H),5.22(s,3H),4.50-4.65(m,12H),4.29(d,J=5.9Hz,3H),4.16(t,J=6.5Hz,3H),3.87-3.95(m,12H),3.83(d,J=7.6Hz,3H),3.73-3.79(m,12H),3.55-3.71(m,36H),3.26-3.30(m,2H),3.14(q,J=6.5Hz,2H),2.18(q,J=7.6Hz,4H),1.98(s,9H),1.53-1.68(m,6H),1.45-1.51(m,11H),1.36-1.43(m,2H),1.29-1.36(m,11H)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(B Amidino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine (l-ag -1) (300 mg, 0.169 mmol) of N,N-dimethylformamide (0.6 ml) and tetrahydrofuran (0.6 ml) were added N,N-diisopropylethylamine (0.118 ml, 0.677 m Mole) and 1-[(6-azidohexyl)oxy]pyrrolidine-2,5-dione (56.0 mg, 0.220 mmol). The reaction was allowed to stir at room temperature for 24 hours. After 24 hours, the reaction was concentrated under reduced pressure. The crude reaction mixture was purified using a CombiFlash Rf (RediSep Gold 24g cartridge eluted with 0 to 20% methanol/dichloromethane gradient) to yield the compound (269 mg, 83%). Method C: 3 minutes LRMS [1/2M + 1 = 956]. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 5.22 (s, 3H), 4.50 - 4.65 (m, 12H), 4.29 (d, J = 5.9 Hz, 3H), 4.16 (t, J=6.5 Hz, 3H), 3.87-3.95 (m, 12H), 3.83 (d, J=7.6 Hz, 3H), 3.73-3.79 (m, 12H), 3.55-3.71 (m, 36H), 3.26-3.30 (m, 2H), 3.14 (q, J = 6.5 Hz, 2H), 2.18 (q, J = 7.6 Hz, 4H), 1.98 (s, 9H), 1.53-1.68 (m, 6H), 1.45-1.51 ( m, 11H), 1.36-1.43 (m, 2H), 1.29-1.36 (m, 11H).

6-疊氮基-N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺(58)6-azido-N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3 -dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2, 3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3- Dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3 -Triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}hexylamine (58)

令6-疊氮基-N-{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)- 7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺(l-ag-5)(25.0mg,0.013毫莫耳)之乙酸(3ml)、甲醇(0.75ml)及水(0.75ml)溶液經加熱至70℃達24小時。經24小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮以生成呈膠之標的化合物(22.7mg,97%)。方法C：3分鐘LRMS[M+1=1791]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),5.21(s,3H),4.51-4.66(m,12H),3.92-4.01(m,6H),3.89(dd,J=10.1,4.7Hz,9H),3.74-3.81(m,9H),3.71(dd,J=10.0,4.1Hz,3H),3.52-3.68(m,42H),3.25-3.30(m,2H),3.08-3.19(m,2H),2.13-2.23(m,4H),1.99(s,9H),1.54-1.69(m,6H),1.49(dt,J=14.4,7.2Hz,2H),1.36-1.44(m,2H),1.32(dd,J=14.8,6.2Hz,2H)。Let 6-azido-N-{6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethinyl))-4, 4-Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxa-10- Trioxane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S) -7-(acetamido)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]- 2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino a solution of -6-oxo-oxyhexyl}hexylamine (l-ag-5) (25.0 mg, 0.013 mmol) in acetic acid (3 ml), methanol (0.75 ml) and water (0.75 ml) was heated to 70 °C for 24 hours. After 24 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure to yield compound (22.7 g, 97%). Method C: 3 minutes LRMS [M+1=1791]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 5.21. (s, 3H), 4.51-4.66 (m, 12H), 3.92-4.01 (m, 6H), 3.89 (dd, J = 10.1) , 4.7 Hz, 9H), 3.74-3.81 (m, 9H), 3.71 (dd, J = 10.0, 4.1 Hz, 3H), 3.52-3.68 (m, 42H), 3.25-3.30 (m, 2H), 3.08- 3.19 (m, 2H), 2.13 - 2.23 (m, 4H), 1.99 (s, 9H), 1.54-1.69 (m, 6H), 1.49 (dt, J = 14.4, 7.2 Hz, 2H), 1.36-1.44 ( m, 2H), 1.32 (dd, J = 14.8, 6.2 Hz, 2H).

1-{[6-(苄氧基)己醯基]氧基}吡咯啶-2,5-二酮(l-al-1)1-{[6-(benzyloxy)hexyl]oxy}pyrrolidine-2,5-dione (l-al-1)

對6-(苄氧基)己酸(參閱文獻 Synlett,(4)：693-697,2004；1400.0mg,6.298毫莫耳)之N,N-二甲基甲醯胺(20ml)溶液先後加入N-羥基琥珀醯亞胺(870mg,7.56毫莫耳)和N-(3-二甲基胺基丙基)-N’-乙基碳二醯亞胺氫氯化物(1480mg,7.56毫莫耳)。令反應物於室溫下經隔夜攪拌。次晨，令該反應物經水驟冷並經二氯甲烷萃取3次。令結合之有機層經飽和碳酸氫鈉溶液和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 40g管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成呈膠之標的化合物(715mg,36%)。方法C：1.5分鐘LRMS[M+Na=342]。1 H NMR(甲醇-d4 )δ：7.22-7.42(m,5H),4.51(s,2H),3.53(t,J=6.4Hz,2H),2.85(s,4H),2.65(t,J=7.4Hz,2H),1.76(quin,J=7.5Hz,2H),1.61-1.71(m,2H),1.47-1.59(m,2H)。6-(benzyloxy)hexanoic acid (See Synlett, (4): 693-697, 2004; 1400.0 mg, 6.298 mmol) of N,N-dimethylformamide (20 ml) followed by N-hydroxysuccinimide (870 mg, 7.56 mmoles and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1480 mg, 7.56 mmol). The reaction was allowed to stir overnight at room temperature. The next morning, the reaction was quenched with water and extracted with dichloromethane three times. The combined organic layers were washed with aq. sodium hydrogen sulfate and brine, dried over sodium sulfate The crude product was purified by CombiFlash Rf (EtOAc (EtOAc) elute Method C: 1.5 minutes LRMS [M+Na=342]. 1 H NMR (methanol-d 4 ) δ: 7.22 - 7.42 (m, 5H), 4.51 (s, 2H), 3.53 (t, J = 6.4 Hz, 2H), 2.85 (s, 4H), 2.65 (t, J = 7.4 Hz, 2H), 1.76 (quin, J = 7.5 Hz, 2H), 1.61-1.71 (m, 2H), 1.47-1.59 (m, 2H).

6-(苄氧基)-N-{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺(l-ag-6)6-(Benzyloxy)-N-{6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4) ,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxa Tridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S) )-7-(acetamido)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl] -2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amine ]--6-sided oxyhexyl} hexylamine (l-ag-6)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(l-ag-1)(200mg,0.113毫莫耳)之N,N-二甲基甲醯胺(0.6ml)和四氫呋喃(0.6ml)溶液加入N,N-二異丙基乙胺(0.0786ml,0.451毫莫耳)和1-{[6-(芾氧基)己醯基]氧基}吡咯啶-2,5-二酮(l-al-1)(46.9mg,0.147毫莫耳)並令反應物於室溫下經攪拌24小時。經24小時後，令該反應物於減壓下經濃縮。令粗產物經CombiFlash Rf(RediSep Gold 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(203mg,91%)。1 H NMR(甲醇-d4 )δ：7.98(s,3H),7.19-7.38(m, 5H),5.23(d,J=1.2Hz,3H),4.52-4.64(m,12H),4.48(s,2H),4.29(d,J=5.9Hz,3H),4.15(t,J=6.4Hz,3H),3.86-3.96(m,12H),3.83(d,J=7.8Hz,3H),3.72-3.80(m,12H),3.54-3.70(m,36H),3.49(t,J=6.4Hz,2H),3.08-3.15(m,2H),2.12-2.26(m,4H),1.98(s,9H),1.51-1.68(m,6H),1.48(s,11H),1.37-1.44(m,2H),1.33(s,11H)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(B Amidino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine (l-ag -1) (200 mg, 0.113 mmol) of N,N-dimethylformamide (0.6 ml) and tetrahydrofuran (0.6 ml) were added N,N-diisopropylethylamine (0.0786 ml, 0.451 m) Mole) and 1-{[6-(decyloxy)hexyl]oxy}pyrrolidine-2,5-dione (l-al-1) (46.9 mg, 0.147 mmol) and reacted The mixture was stirred at room temperature for 24 hours. After 24 hours, the reaction was concentrated under reduced pressure. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 7.19-7.38 (m, 5H), 5.23 (d, J = 1.2 Hz, 3H), 4.52-4.64 (m, 12H), 4.48 ( s, 2H), 4.29 (d, J = 5.9 Hz, 3H), 4.15 (t, J = 6.4 Hz, 3H), 3.86-3.96 (m, 12H), 3.83 (d, J = 7.8 Hz, 3H), 3.72-3.80 (m, 12H), 3.54-3.70 (m, 36H), 3.49 (t, J = 6.4 Hz, 2H), 3.08-3.15 (m, 2H), 2.12-2.26 (m, 4H), 1.98 ( s, 9H), 1.51-1.68 (m, 6H), 1.48 (s, 11H), 1.37-1.44 (m, 2H), 1.33 (s, 11H).

6-(苄氧基)-N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺(59)6-(Benzyloxy)-N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2) ,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1, 2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2, 3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2 ,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}hexylamine (59)

令6-(苄氧基)-N-{6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)- 7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺(l-ag-6)(180.0mg,0.0911毫莫耳)之乙酸(6.0ml)、甲醇(1.5ml)及水(1.5ml)溶液經加熱至70℃達24小時。經24小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮以生成呈膠之標的化合物(164.0mg,97.0%)。方法C：3分鐘LRMS[1/2M=928]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),7.25-7.39(m,5H),5.21(s,3H),4.52-4.66(m,12H),4.48(s,2H),3.92-3.99(m,6H),3.84-3.91(m,9H),3.74-3.81(m,9H),3.71(dd,J=9.8,4.3Hz,3H),3.54-3.67(m,42H),3.49(t,J=6.4Hz,2H),3.08-3.17(m,2H),2.13-2.22(m,4H),1.99(s,9H),1.51-1.68(m,6H),1.48(t,J=7.4Hz,2H),1.39(dt,J=15.3,7.8Hz,2H),1.26-1.35(m,2H)。Let 6-(benzyloxy)-N-{6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethinyl))- 4,4-Dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxy Heterotridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R, 8S)-7-(acetamido)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl ]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl) Amino]-6-oxo-oxyhexyl}hexylamine (l-ag-6) (180.0 mg, 0.0911 mmol) of acetic acid (6.0 ml), methanol (1.5 ml) and water (1.5 ml) Heat to 70 ° C for 24 hours. After 24 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure to yield compound (164.0mg, 97.0%). Method C: 3 minutes LRMS [1/2 M = 928]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 7.25-7.39 (m, 5H), 5.21. (s, 3H), 4.52-4.66 (m, 12H), 4.48 (s, 2H), 3.92-3.99 (m, 6H), 3.84-3.91 (m, 9H), 3.74-3.81 (m, 9H), 3.71 (dd, J = 9.8, 4.3 Hz, 3H), 3.54-3.67 (m, 42H), 3.49 (t, J = 6.4 Hz, 2H), 3.08-3.17 (m, 2H), 2.13 - 2.22 (m, 4H), 1.99 (s, 9H), 1.51-1.68 (m, 6H), 1.48 (t, J = 7.4 Hz, 2H), 1.39 (dt, J = 15.3, 7.8 Hz, 2H), 1.26-1.35 (m, 2H).

乙酸(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2-(乙醯氧基)-1-{13-[4-(4,4-雙{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-6,13- 二側氧基-20-苯基-2,19-二氧雜-5,12-二氮雜二十烷-1-基)-1H-1,2,3-***-1-基]-2,5,8,11-四氧雜十三烷-1-基}-6,8-二氧雜雙環[3.2.1]辛-3-基酯(l-am-1)Acetic acid (1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-2-(ethyloxy)-1-{13-[4-(4,4-double{[(1- {1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethyloxy)-6,8-dioxabicyclo[3.2.1] Oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}- 6,13- Bilateral oxy-20-phenyl-2,19-dioxa-5,12-diazaicosyl-1-yl)-1H-1,2,3-triazol-1-yl]- 2,5,8,11-tetraoxatridecyl-1-yl}-6,8-dioxabicyclo[3.2.1]oct-3-yl ester (l-am-1)

令6-(苄氧基)-N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺(59)(130mg,0.07毫莫耳)溶解於(3ml,40毫莫耳)並於室溫下加入乙酸酐(0.198ml,2.10毫莫耳)。隨後令反應物經隔夜加熱至50℃。次晨，令該反應物於減壓下經濃縮。令粗產物經CombiFlash Rf(RediSep Gold 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(130.0mg,88%)。方法C： 3分鐘LRMS[1/2M=1054]。1 H NMR(甲醇-d4 )δ：7.98(s,3H),7.16-7.39(m,5H),5.44(d,J=4.3Hz,3H),5.32(s,3H),5.10(dd,J=10.5,4.3Hz,3H),4.52-4.60(m,12H),4.48(s,2H),4.18(d,J=10.5Hz,3H),3.99(d,J=8.2Hz,3H),3.89(t,J=5.1Hz,6H),3.70-3.81(m,12H),3.52-3.67(m,39H),3.49(t,J=6.2Hz,2H),3.13(q,J=6.6Hz,2H),2.13-2.21(m,13H),1.94(d,J=1.6Hz,18H),1.51-1.68(m,6H),1.45-1.50(m,2H),1.37-1.43(m,2H),1.28-1.35(m,2H)。Let 6-(benzyloxy)-N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-)- 2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1 ,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2 ,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1, 2,3-Triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxooxyhexyl}hexylamine (59) (130 mg, 0.07 mmol) dissolved (3 ml, 40 mmol) and acetic anhydride (0.198 ml, 2.10 mmol) were added at room temperature. The reaction was then allowed to warm to 50 °C overnight. The next morning, the reaction was concentrated under reduced pressure. The crude product was purified by CombiFlash Rf (EtOAc EtOAc (EtOAc) elute Method C: 3 minutes LRMS [1/2M = 1054]. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 7.16-7.39 (m, 5H), 5.44 (d, J = 4.3 Hz, 3H), 5.32 (s, 3H), 5.10 (dd, J = 10.5, 4.3 Hz, 3H), 4.52-4.60 (m, 12H), 4.48 (s, 2H), 4.18 (d, J = 10.5 Hz, 3H), 3.99 (d, J = 8.2 Hz, 3H), 3.89 (t, J = 5.1 Hz, 6H), 3.70-3.81 (m, 12H), 3.52-3.67 (m, 39H), 3.49 (t, J = 6.2 Hz, 2H), 3.13 (q, J = 6.6 Hz) , 2H), 2.13 - 2.21 (m, 13H), 1.94 (d, J = 1.6 Hz, 18H), 1.51-1.68 (m, 6H), 1.45-1.50 (m, 2H), 1.37-1.43 (m, 2H) ), 1.28-1.35 (m, 2H).

N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-羥基己醯胺(l-an-1)N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]methyl}propan-2-yl)amino]-6-oxooxyhexyl}-6-hydroxyhexylamine (l-an-1)

令乙酸(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2-(乙醯氧基)-1-{13-[4-(4,4-雙{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-6,13-二側氧基-20-苯基-2,19-二氧雜-5,12-二氮雜二十烷-1-基)-1H-1,2,3-***-1-基]-2,5,8,11-四氧雜十三烷-1-基}-6,8-二氧雜雙環[3.2.1]辛-3-基酯(l-am-1)(110mg,0.0522毫莫耳)溶解於甲醇(10.0ml)並令溶液隨後通過H立方體(使用10% Pd/C(小筒)；使用下述參數：溫度：60℃；流速：1.0ml/分鐘；壓力=全部H2 (1巴))。收集溶液並經減壓下濃縮以生成呈膠之標的化合物(91.6mg,87%)。方法C：3分鐘LRMS[1/2M=1009]。1 H NMR(甲醇-d4 )δ：7.98(s,3H),5.44(d,J=4.3Hz,3H),5.32(s,3H),5.10(dd,J=10.5,4.3Hz,3H),4.50-4.64(m,12H),4.18(d, J=10.5Hz,3H),3.99(d,J=8.2Hz,3H),3.90(t,J=4.9Hz,6H),3.71-3.82(m,9H),3.44-3.66(m,44H),3.08-3.19(m,2H),2.16-2.22(m,4H),2.15(s,9H),1.94(d,J=1.2Hz,18H),1.44-1.68(m,8H),1.27-1.42(m,4H)。Let acetic acid (1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-2-(ethyloxy)-1-{13-[4-(4,4-double {[(1) -{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethyloxy)-6,8-dioxabicyclo[3.2.1 Octyl-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl} -6,13-di- oxy-20-phenyl-2,19-dioxa-5,12-diazaecheo-1-yl)-1H-1,2,3-triazole- 1-yl]-2,5,8,11-tetraoxatridecyl-1-yl}-6,8-dioxabicyclo[3.2.1]oct-3-yl ester (l-am-1 (110 mg, 0.0522 mmol) dissolved in methanol (10.0 ml) and allowed to pass through H cube (using 10% Pd/C (small cartridge); using the following parameters: temperature: 60 ° C; flow rate: 1.0 ml / Minutes; pressure = all H 2 (1 bar)). The solution was collected and concentrated under reduced pressure to give compound (91.6 mg, 87%). Method C: 3 minutes LRMS [1/2M = 1009]. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 5.44 (d, J = 4.3 Hz, 3H), 5.32 (s, 3H), 5.10 (dd, J = 10.5, 4.3 Hz, 3H) , 4.50-4.64 (m, 12H), 4.18 (d, J = 10.5 Hz, 3H), 3.99 (d, J = 8.2 Hz, 3H), 3.90 (t, J = 4.9 Hz, 6H), 3.71-3.82 ( m, 9H), 3.44 - 3.66 (m, 44H), 3.08-3.19 (m, 2H), 2.16 - 2.22 (m, 4H), 2.15 (s, 9H), 1.94 (d, J = 1.2 Hz, 18H) , 1.44-1.68 (m, 8H), 1.27-1.42 (m, 4H).

乙酸(1S,2R,3R,4R,5S)-4-(乙醯胺基)-1-{13-[4-({3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-({6-[(6-羥基己醯基)胺基]己醯基}胺基)丙氧基}甲基)-1H-1,2,3-***-1-基]-2,5,8,11-四氧雜十三烷-1-基}-3-(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-2-基酯(60)Acetic acid (1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-1-{13-[4-({3-[(1-{1-[(1S,2R,3R,4R) ,5S)-4-(ethylamino)-2,3-bis(ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R) ,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethoxycarbonyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2 ,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-({6-[( 6-hydroxyhexyl)amino]hexanyl}amino)propoxy}methyl)-1H-1,2,3-triazol-1-yl]-2,5,8,11-tetra Oxatridecyl-1-yl}-3-(ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl ester (60)

令6-(苄氧基)-N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)- 4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺(l-an-1)(31.0mg,0.017毫莫耳)溶解於甲醇(5ml)並令溶液隨後通過H立方體(使用10% Pd/C(小筒)；使用下述參數：溫度：60℃；流速：1.0ml/分鐘；壓力=全部H2 (1巴))。收集溶液並經減壓下濃縮以生成呈膠之標的化合物(7.9mg,27%)。方法C：3分鐘LRMS[M+1=1766]。1 H NMR(甲醇-d4 )δ：7.99(s,3H),5.21(s,3H),4.49-4.63(m,12H),3.92-4.00(m,6H),3.89(dd,J=10.3,4.5Hz,9H),3.74-3.79(m,9H),3.71(dd,J=9.8,4.3Hz,3H),3.53-3.67(m,44H),3.02-3.16(m,2H),2.18(td,J=7.3,3.3Hz,4H),1.99(s,9H),1.44-1.72(m,8H),1.25-1.42(m,4H)。Let 6-(benzyloxy)-N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4- 4-ethylamino)- 2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1 ,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2 ,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1, 2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}hexylamine (l-an-1) (31.0 mg, 0.017 Mol) dissolved in methanol (5 ml) and allowed to pass through the H cube (using 10% Pd/C (small cartridge); using the following parameters: temperature: 60 ° C; flow rate: 1.0 ml/min; pressure = all H 2 (1 bar)). The solution was collected and concentrated under reduced pressure to yield compound (yield: 7.9 mg, 27%). Method C: 3 minutes LRMS [M+1 = 1766]. 1 H NMR (methanol-d 4 ) δ: 7.99 (s, 3H), 5.21 (s, 3H), 4.49-4.63 (m, 12H), 3.92-4.00 (m, 6H), 3.89 (dd, J = 10.3) , 4.5Hz, 9H), 3.74 - 3.79 (m, 9H), 3.71 (dd, J = 9.8, 4.3 Hz, 3H), 3.53-3.67 (m, 44H), 3.02-3.16 (m, 2H), 2.18 ( Td, J = 7.3, 3.3 Hz, 4H), 1.99 (s, 9H), 1.44-1.72 (m, 8H), 1.25-1.42 (m, 4H).

[6-({6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺基)-6-側氧基己基]胺甲酸苄 酯(l-ag-7)[6-({6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(B Amidino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-side Oxyhexyl}amino)-6-oxooxyhexyl] benzyl carbamate Ester (l-ag-7)

對6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺(l-ag-1)(222mg,0.125毫莫耳)之N,N-二甲基甲醯胺(1.5ml)和四氫呋喃(1.0ml)溶液加入N,N-二異丙基乙胺(0.0873ml,0.501毫莫耳)和{6-[(2,5-二側氧基吡咯啶-1-基)氧基]-6-側氧基己基}胺甲酸苄酯(參閱文獻Journal of Heterocyclic Chemistry,23(3),901-3,1986；68.1mg,0.188毫莫耳)。令反應物於室溫下經攪拌24小時。經24 小時後，令該反應物於減壓下經濃縮。使用CombiFlash Rf(RediSep Gold 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化粗反應混合物以生成呈膠之標的化合物(250mg,99%)。方法C：3分鐘LRMS[1/2M+1=1010]。1 H NMR(甲醇-d4 )δ：7.98(s,3H),7.22-7.40(m,5H),5.22(d,J=1.2Hz,3H),5.06(s,2H),4.51-4.61(m,12H),4.29(d,J=5.9Hz,3H),4.16(t,J=6.4Hz,3H),3.86-3.96(m,12H),3.83(d,J=7.8Hz,3H),3.73-3.79(m,12H),3.53-3.70(m,36H),3.04-3.19(m,4H),2.17(t,J=7.4Hz,4H),1.98(s,9H),1.58(td,J=14.5,7.6Hz,4H),1.48(s,13H),1.33(s,13H)。6-Amino-N-(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(B Amidino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine (l-ag -1) (222 mg, 0.125 mmol) of N,N-dimethylformamide (1.5 ml) and tetrahydrofuran (1.0 ml) were added N,N-diisopropylethylamine (0.0873 ml, 0.501 m Mohr) and Benzyl {6-[(2,5-di-oxypyrrolidin-1-yl)oxy]-6-oxo-oxyhexyl}carbamate (see Journal of Heterocyclic Chemistry, 23(3), 901- 3,1986; 68.1 mg, 0.188 mmol. The reaction was allowed to stir at room temperature for 24 hours. After 24 hours, the reaction was concentrated under reduced pressure. The crude reaction mixture was purified using a CombiFlash Rf (RediSep Gold 12g cartridge) eluting with 0 to 20% methanol/dichloromethane gradient to afford compound (250 mg, 99%). Method C: 3 minutes LRMS [1/2M + 1 = 1010]. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 7.22-7.40 (m, 5H), 5.22 (d, J = 1.2 Hz, 3H), 5.06 (s, 2H), 4.51-4.61 ( m, 12H), 4.29 (d, J = 5.9 Hz, 3H), 4.16 (t, J = 6.4 Hz, 3H), 3.86-3.96 (m, 12H), 3.83 (d, J = 7.8 Hz, 3H), 3.73-3.79 (m, 12H), 3.53-3.70 (m, 36H), 3.04-3.19 (m, 4H), 2.17 (t, J = 7.4 Hz, 4H), 1.98 (s, 9H), 1.58 (td, J = 14.5, 7.6 Hz, 4H), 1.48 (s, 13H), 1.33 (s, 13H).

[6-({6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺基)-6-側氧基己基]胺甲酸苄酯(61)[6-({6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy- 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 ,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole- 4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}amino)-6-oxo-oxyhexyl] benzyl carbamate (61)

令[6-({6-[(1,3-雙[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(乙醯胺基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺基)-6-側氧基己基]胺甲酸苄酯(l-ag-7)(250.0mg,0.124毫莫耳)之乙酸(8ml)、甲醇(2ml)及水(2ml)溶液經加熱至70℃達36小時。經36小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經甲苯稀釋並經減壓下濃縮。令粗產物再次經甲苯稀釋並經減壓下濃縮以生成呈膠之標的化合物(225mg,96%)。方法C：3分鐘LRMS[1/2M+1=950]。1 H NMR(甲醇-d4 )δ：7.98(s,3H),7.22-7.41(m,5H),5.21(s,3H),5.05(s,2H),4.57(t,J=5.0Hz,6H),4.55(s,6H),3.92-4.00(m,6H),3.83-3.91(m,9H),3.73-3.78(m,9H), 3.68-3.72(m,J=10.0,4.1Hz,3H),3.52-3.68(m,42H),3.05-3.17(m,4H),2.16(t,J=7.3Hz,4H),1.98(s,9H),1.57-1.65(m,2H),1.53-1.57(m,2H),1.43-1.52(m,4H),1.24-1.39(m,4H)。Let [6-({6-[(1,3-bis[(1-{1-[(1S,2R,6R,7R,8S)-7-(ethylamino)-4,4-dimethyl Base-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5,8,11-tetraoxatridecane-13 -yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,6R,7R,8S)-7-(( Ethylamino)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl]-2,5, 8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6- Benzyloxyhexyl}amino)-6-oxo-oxyhexyl] benzyl carbamate (l-ag-7) (250.0 mg, 0.124 mmol) of acetic acid (8 ml), methanol (2 ml) and water (2 ml) The solution was heated to 70 ° C for 36 hours. After 36 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with toluene and concentrated under reduced pressure. The crude product was again diluted with toluene and concentrated under reduced pressure to yield compound ( 225 mg, 96%). Method C: 3 minutes LRMS [1/2M + 1 = 950]. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 7.22-7.41 (m, 5H), 5.21. (s, 3H), 5.05 (s, 2H), 4.57 (t, J = 5.0 Hz, 6H), 4.55 (s, 6H), 3.92-4.00 (m, 6H), 3.83-3.91 (m, 9H), 3.73-3.78 (m, 9H), 3.68-3.72 (m, J = 10.0, 4.1 Hz, 3H), 3.52-3.68 (m, 42H), 3.05-3.17 (m, 4H), 2.16 (t, J = 7.3 Hz, 4H), 1.98 (s, 9H), 1.57-1.65 (m, 2H), 1.53 -1.57 (m, 2H), 1.43-1.52 (m, 4H), 1.24-1.39 (m, 4H).

乙酸6-胺基-N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺酯(62)Acetate 6-Amino-N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3 -dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2, 3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3- Dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3 -Triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}hexylamine (62)

令[6-({6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1- {1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺基)-6-側氧基己基]胺甲酸苄酯(61)(200mg,0.105毫莫耳)溶解於甲醇(20ml)和乙酸(0.024ml,0.421毫莫耳)並令溶液隨後通過H立方體(使用10% Pd/C(小筒)；使用下述參數：溫度：50℃；流速：1.0ml/分鐘；壓力=全部H2 (1巴))。收集溶液並經減壓下濃縮以生成呈膠之標的化合物(148mg,77%)。方法C：3分鐘LRMS[M+45(甲酸)=1809]。1 H NMR(甲醇-d4 )δ：8.02(s,3H),5.23(s,3H),4.59-4.63(m,6H),4.58(s,6H),3.97(dd,J=9.6,5.3Hz,6H),3.91(dd,J=11.3,4.7Hz,9H),3.76-3.82(m,9H),3.73(dd,J=10.1,4.3Hz,3H),3.56-3.70(m,42H),3.16(t,J=6.8Hz,2H),2.93(t,J=7.6Hz,2H),2.16-2.29(m,4H),2.01(s,9H),1.92(s,3H),1.62-1.74(m,4H),1.54-1.61(m,2H),1.46-1.53(m,2H),1.39-1.45(m,2H),1.29-1.38(m,2H)。Let [6-({6-[(1,3-bis[(1-S1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy) -6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-three Zin-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy- 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole -4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}amino)-6-oxo-oxyhexyl] benzyl carbamate (61) (200 mg, 0.105 mmoles dissolved in methanol (20 ml) and acetic acid (0.024 ml, 0.421 mmol) and the solution was then passed through H cube (using 10% Pd/C (small cartridge); using the following parameters: temperature: 50 ° C Flow rate: 1.0 ml/min; pressure = all H 2 (1 bar)). The solution was collected and concentrated under reduced pressure to yield compound (148 mg, 77%). Method C: 3 minutes LRMS [M+45 (carboxylic acid) = 1809]. 1 H NMR (methanol-d 4 ) δ: 8.02 (s, 3H), 5.23 (s, 3H), 4.59-4.63 (m, 6H), 4.58 (s, 6H), 3.97 (dd, J = 9.6, 5.3 Hz,6H), 3.91 (dd, J=11.3, 4.7 Hz, 9H), 3.76-3.82 (m, 9H), 3.73 (dd, J = 10.1, 4.3 Hz, 3H), 3.56-3.70 (m, 42H) , 3.16 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.16-2.29 (m, 4H), 2.01 (s, 9H), 1.92 (s, 3H), 1.62 1.74 (m, 4H), 1.54-1.61 (m, 2H), 1.46-1.53 (m, 2H), 1.39-1.45 (m, 2H), 1.29-1.38 (m, 2H).

[(1S,2R,6R,7R,8S)-7-疊氮基-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]甲醇(l-d-1)[(1S, 2R, 6R, 7R, 8S)-7-azido-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~] Undec-1-yl]methanol (ld-1)

對(1S,2R,3R,4R,5S)-4-疊氮基-1-(羥基甲基)-6,8-二氧 雜雙環[3.2.1]辛烷-2,3-二醇(1)(2.52g,11.61毫莫耳)之N,N-二甲基甲醯胺(21ml)溶液先後加入2 2-二甲氧基丙烷(9.0ml,69.6毫莫耳)和(1S)-(+)-10-樟腦磺酸(1.08g,4.65毫莫耳)。令反應物經加熱至70℃達24小時。經24小時後，令該反應物經冷卻至室溫且隨後先後加入甲醇(5ml)和三乙胺(0.22ml,1.55毫莫耳)並令溶液經攪拌10分鐘且隨後經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 80g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成不純之標的化合物。令該粗產物經CombiFlash Rf(RediSep Gold 40g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成標的化合物(2419mg,81%)。1 H NMR(甲醇-d4 )δ：5.42(d,J=1.6Hz,1H),4.34-4.43(m,2H),3.88-3.98(m,3H),3.81-3.87(m,1H),3.37(dd,J=6.2,1.6Hz,1H),1.54(s,3H),1.42(s,3H)。(1S, 2R, 3R, 4R, 5S)-4-azido-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3-diol ( 1) (2.52 g, 11.61 mmol) of N,N-dimethylformamide (21 ml) was added 2 2-dimethoxypropane (9.0 ml, 69.6 mmol) and (1S)- (+)-10-camphorsulfonic acid (1.08 g, 4.65 mmol). The reaction was allowed to warm to 70 ° C for 24 hours. After 24 hours, the reaction was cooled to rt then MeOH (5 mL) and triethylamine (0.22 <RTIgt; The crude product was purified via a CombiFlash Rf (RediSep Gold 80g cartridge column; eluted with 0 to 20% methanol/dichloromethane gradient) to yield the crude compound. The crude product was purified with EtOAc EtOAc EtOAc (EtOAc) 1 H NMR (methanol-d 4 ) δ: 5.42 (d, J = 1.6 Hz, 1H), 4.34 - 4.43 (m, 2H), 3.88-3.98 (m, 3H), 3.81-3.87 (m, 1H), 3.37 (dd, J = 6.2, 1.6 Hz, 1H), 1.54 (s, 3H), 1.42 (s, 3H).

(1S,2R,6R,7R,8S)-7-疊氮基-4,4-二甲基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷(l-d-2)(1S, 2R, 6R, 7R, 8S)-7-azido-4,4-dimethyl-1-(15-phenyl-2,5,8,11,14-pentaoxapentadecane -1-yl)-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undecane (ld-2)

於室溫下對[(1S,2R,6R,7R,8S)-7-疊氮基-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基]甲醇(l-d-1)(490mg,1.90毫莫耳)之四氫呋喃(5ml)溶液加入氫化鈉 60%礦物油分散液(127mg,3.2毫莫耳)。令反應物於氮氣下經攪拌30分鐘並隨後加入13-碘-1-苯基-2,5,8,11-四氧雜十三烷(1130mg,2.86毫莫耳)之四氫呋喃(2ml)溶液。令反應物於室溫下經隔夜攪拌。次晨(經18小時)，令該反應物經水驟冷並經乙酸乙酯萃取。令該水層再經乙酸乙酯沖洗2次。令結合之有機層經水和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(ISCO RediSep Gold 40g矽膠管柱；經0至100%乙酸乙酯/庚烷梯度洗提)純化以生成呈膠之標的化合物(336.0mg,34%)。方法C：1.5分鐘LRMS[M+Na=546]。1 H NMR(甲醇-d4 )δ：7.17-7.47(m,5H),5.35(d,J=1.6Hz,1H),4.55(s,2H),4.32-4.37(m,1H),4.25-4.32(m,1H),3.92(d,J=10.1Hz,1H),3.88(d,J=8.2Hz,1H),3.73-3.80(m,2H),3.55-3.71(m,17H),1.49(s,3H),1.36(s,3H)。[(1S,2R,6R,7R,8S)-7-azido-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~ at room temperature 2,6~]undecyl-1-yl]methanol (ld-1) (490 mg, 1.90 mmol) in tetrahydrofuran (5 ml) was added to sodium hydride 60% mineral oil dispersion (127 mg, 3.2 mmol) . The reaction was stirred under nitrogen for 30 min and then a solution of 13-iodo-1-phenyl-2,5,8,11-tetraoxatridecane (1130 mg, 2.86 mmol) in THF (2 mL) . The reaction was allowed to stir overnight at room temperature. The next morning (over 18 hours) the reaction was quenched with water and extracted withEtOAc. The aqueous layer was washed twice more with ethyl acetate. The combined organic layers were washed with water and brine, dried over sodium sulfate and filtered and evaporated. The crude product was purified with EtOAc (EtOAc) elute Method C: 1.5 minutes LRMS [M+Na=546]. 1 H NMR (methanol-d 4 ) δ: 7.17-7.47 (m, 5H), 5.35 (d, J = 1.6 Hz, 1H), 4.55 (s, 2H), 4.32-4.37 (m, 1H), 4.25- 4.32 (m, 1H), 3.92 (d, J = 10.1 Hz, 1H), 3.88 (d, J = 8.2 Hz, 1H), 3.73 - 3.80 (m, 2H), 3.55 - 3.71 (m, 17H), 1.49 (s, 3H), 1.36 (s, 3H).

[(1S,2R,6R,7R,8S)-1-(13-羥基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]胺甲酸三級丁酯(l-ao-1)[(1S, 2R, 6R, 7R, 8S)-1-(13-hydroxy-2,5,8,11-tetraoxatridec-1-yl)-4,4-dimethyl-3, 5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]carbamic acid tert-butyl butyl ester (l-ao-1)

於反應器(50ml)中令起始物(1S,2R,6R,7R,8S)-7-疊氮基-4,4-二甲基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷(l-d-2)(310.0 mg,0.592毫莫耳)溶解於甲醇(6ml)並隨後加入二碳酸二(三級丁酯)(162mg,0.74毫莫耳)和10% Pd/C(50%濕wt/wt,100.0mg,0.940毫莫耳)。密封該反應器並令反應物經氮氣(50psi)清洗3次且隨後經氫氣(50psi)清洗2次並填充氫氣(50psi)且經隔夜攪拌。次晨(24小時)，令反應物經通過寅氏鹽塞過濾並經甲醇沖洗。令濾液經減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(304mg,100%)。方法C：3分鐘LRMS[M+Na=530]。1 H NMR(甲醇-d4 )δ：5.22(s,1H),4.28(d,J=5.9Hz,1H),4.11(t,J=6.4Hz,1H),3.93(d,J=10.1Hz,1H),3.80-3.85(m,1H),3.76(d,J=6.2Hz,1H),3.74(d,J=3.9Hz,1H),3.60-3.71(m,15H),3.53-3.59(m,2H),1.50(s,3H),1.45(s,9H),1.34(s,3H)。Starting material (1S, 2R, 6R, 7R, 8S)-7-azido-4,4-dimethyl-1-(15-phenyl-2,5,8) in a reactor (50 ml) ,11,14-pentaoxapentadecan-1-yl)-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undecane (ld-2) (310.0 Mg, 0.592 mmol, dissolved in methanol (6 ml) and then added di(tertiary butyl dicarbonate) (162 mg, 0.74 mmol) and 10% Pd/C (50% wet wt/wt, 100.0 mg, 0.940 millimoles). The reactor was sealed and the reaction was washed three times with nitrogen (50 psi) and then twice with hydrogen (50 psi) and filled with hydrogen (50 psi) and stirred overnight. The next morning (24 hours), the reaction was filtered through a pad of Celite and rinsed with methanol. The filtrate was concentrated under reduced pressure. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc (EtOAc) elute Method C: 3 minutes LRMS [M+Na=530]. 1 H NMR (methanol-d 4 ) δ: 5.22 (s, 1H), 4.28 (d, J = 5.9 Hz, 1H), 4.11 (t, J = 6.4 Hz, 1H), 3.93 (d, J = 10.1 Hz) , 1H), 3.80-3.85 (m, 1H), 3.76 (d, J = 6.2 Hz, 1H), 3.74 (d, J = 3.9 Hz, 1H), 3.60-3.71 (m, 15H), 3.53-3.59 ( m, 2H), 1.50 (s, 3H), 1.45 (s, 9H), 1.34 (s, 3H).

甲磺酸1-{(1S,2R,6R,7R,8S)-7-[(三級丁氧羰基)胺基]-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基}-2,5,8,11-四氧雜十三烷-13-基酯(l-ap-1)1-{(1S,2R,6R,7R,8S)-7-[(tertiary butoxycarbonyl)amino]-4,4-dimethyl-3,5,9,11-tetraoxymethanesulfonate Heterotricyclo[6.2.1.0~2,6~]undec-1-yl}-2,5,8,11-tetraoxatridecane-13-yl ester (l-ap-1)

對[(1S,2R,6R,7R,8S)-1-(13-羥基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]胺甲酸三級丁酯(l-ao-1)(300.0mg,0.591毫莫 耳)之二氯甲烷(2ml)溶液加入三乙胺(0.332ml,2.36毫莫耳)並經冰浴冷卻至0℃且隨後加入甲磺醯氯(0.055ml,0.71毫莫耳)。令反應物緩慢回溫至室溫並於室溫下經攪拌20小時。經20小時後，令該反應物經水驟冷並經萃取。分離相層並令水層經二氯甲烷萃取1次。令結合之有機層經鹽水沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮以生成呈油之標的化合物(339mg,98%)。方法C：3分鐘LRMS[M+Na=608]。1 H NMR(甲醇-d4 )δ：5.22(s,1H),4.33-4.43(m,2H),4.28(d,J=5.9Hz,1H),4.11(t,J=6.4Hz,1H),3.93(d,J=10.1Hz,1H),3.80-3.86(m,1H),3.72-3.79(m,4H),3.61-3.70(m,12H),3.58(d,J=5.9Hz,1H),3.11(s,3H),1.50(s,3H),1.45(s,9H),1.34(s,3H)。For [(1S,2R,6R,7R,8S)-1-(13-hydroxy-2,5,8,11-tetraoxatridec-1-yl)-4,4-dimethyl-3 ,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]amino acid tert-butyl butyl ester (l-ao-1) (300.0 mg, 0.591 mmol) A solution of the methylene chloride (2 ml) was added triethylamine (0.332 mL, 2.36 mmol) and cooled to 0 &lt;0&gt;C and then methanesulfonium chloride (0.055 ml, 0.71 mmol). The reaction was slowly warmed to room temperature and stirred at room temperature for 20 hours. After 20 hours, the reaction was quenched with water and extracted. The phase layer was separated and the aqueous layer was extracted once with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered and evaporated. Method C: 3 minutes LRMS [M+Na=608]. 1 H NMR (methanol-d 4 ) δ: 5.22 (s, 1H), 4.33-4.43 (m, 2H), 4.28 (d, J = 5.9 Hz, 1H), 4.11 (t, J = 6.4 Hz, 1H) , 3.93 (d, J = 10.1 Hz, 1H), 3.80-3.86 (m, 1H), 3.72-3.79 (m, 4H), 3.61-3.70 (m, 12H), 3.58 (d, J = 5.9 Hz, 1H) ), 3.11 (s, 3H), 1.50 (s, 3H), 1.45 (s, 9H), 1.34 (s, 3H).

[(1S,2R,6R,7R,8S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]胺甲酸三級丁酯(l-aq-1)[(1S,2R,6R,7R,8S)-1-(13-azido-2,5,8,11-tetraoxatridec-1-yl)-4,4-dimethyl- 3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-7-yl]carbamic acid tert-butyl butyl ester (l-aq-1)

對甲磺酸1-{(1S,2R,6R,7R,8S)-7-[(三級丁氧羰基)胺基]-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基}-2,5,8,11-四氧雜十三烷-13-基酯(l-ap-1)(339mg,0.579毫莫耳)之N,N-二甲基甲醯胺(1.5ml)溶液加入疊氮化鈉(67.7mg,1.04毫莫耳)並令反應物於密封之微波小管 (5ml)中經隔夜加熱至100℃。經18小時後，令該反應物經冷卻至室溫並令該反應物經水稀釋並經乙酸乙酯萃取3次。令結合之有機層經水和鹽水沖洗，置於硫酸鈉上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(246mg,80%)。1 H NMR(甲醇-d4 )δ：5.24(s,1H),4.30(d,J=5.9Hz,1H),4.13(t,J=6.4Hz,1H),3.95(d,J=9.8Hz,1H),3.82-3.88(m,1H),3.75-3.80(m,2H),3.53-3.74(m,15H),3.39(t,J=4.9Hz,2H),1.52(s,3H),1.47(s,9H),1.36(s,3H)。1-{(1S,2R,6R,7R,8S)-7-[(tertiary butoxycarbonyl)amino]-4,4-dimethyl-3,5,9,11-tetramethanesulfonic acid Oxatricyclo[6.2.1.0~2,6~]undec-1-yl}-2,5,8,11-tetraoxatridecane-13-yl ester (l-ap-1) 339 mg, 0.579 mmol of N,N-dimethylformamide (1.5 ml) was added to sodium azide (67.7 mg, 1.04 mmol) and the reaction was taken in a sealed microwave vial (5 ml) Heated to 100 ° C overnight. After 18 hours, the reaction was allowed to cool to rt and then diluted with water and th The combined organic layers were washed with water and brine, dried over sodium sulfate and filtered and evaporated. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc EtOAc. 1 H NMR (methanol-d 4 ) δ: 5.24 (s, 1H), 4.30 (d, J = 5.9 Hz, 1H), 4.13 (t, J = 6.4 Hz, 1H), 3.95 (d, J = 9.8 Hz) , 1H), 3.82-3.88 (m, 1H), 3.75-3.80 (m, 2H), 3.53-3.74 (m, 15H), 3.39 (t, J = 4.9 Hz, 2H), 1.52 (s, 3H), 1.47 (s, 9H), 1.36 (s, 3H).

{(1S,2R,6R,7R,8S)-1-[13-(4-{[2-{[4-(苄氧基)丁醯基]胺基}-3-{[1-(1-{(1S,2R,6R,7R,8S)-7-[(三級丁氧羰基)胺基]-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基}-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基]甲氧基}-2-({[1-(1-{(1S,2R,6R,7R,8S)-7-[(三級丁氧羰基)胺基]-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基}-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基]甲氧基}甲基)丙氧基]甲基}-1H-1,2,3-***-1-基)-2,5,8,11-四氧雜十三烷-1-基]-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基}胺甲酸三級丁酯(l-ar-1){(1S,2R,6R,7R,8S)-1-[13-(4-{[2-{[4-(benzyloxy)butanyl)amino}-3-{[1-(1-{ (1S, 2R, 6R, 7R, 8S)-7-[(tertiary butoxycarbonyl)amino]-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2. 1.0~2,6~]undec-1-yl}-2,5,8,11-tetraoxatridecane-13-yl)-1H-1,2,3-triazol-4-yl Methoxy}-2-({[1-(1-{(1S,2R,6R,7R,8S)-7-[(tertiary butoxycarbonyl)amino]-4,4-dimethyl -3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl}-2,5,8,11-tetraoxatridecane-13- -1H-1,2,3-triazol-4-yl]methoxy}methyl)propoxy]methyl}-1H-1,2,3-triazol-1-yl)-2 ,5,8,11-tetraoxatridec-1-yl]-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~] Undecyl-7-yl}carbamic acid tert-butyl butyl ester (l-ar-1)

對配備攪拌棒之小管(20ml)載入4-(芾氧基)-N-{1,3-雙(丙-2-炔-1-基氧)-2-[(丙-2-炔-1-基氧)甲基]丙-2-基}丁醯胺(l-v-1)(45.0mg,0.11毫莫耳)並加入[(1S,2R,6R,7R,8S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基]胺甲酸三級丁酯(l-aq-1)(192mg,0.361毫莫耳)之三級丁醇(3ml)和水(1.5ml，去離子水)溶液。令反應物經氮氣清洗5分鐘並隨後加入抗壞血酸鈉(66.3mg,0.328毫莫耳)且逐滴加入硫酸銅(II)(5.24mg,0.0328毫莫耳)之水(500ul，去離子水)溶液。令反應物於室溫下經攪拌20小時。經20小時後，令該反應物經冷卻至室溫並藉由將反應混合物加入至飽和氯化銨溶液(30ml)和濃氫氧化銨溶液(2ml)使反應驟冷且經二氯甲烷(15ml)萃取3次。令結合之有機層置於硫 酸鈉上乾燥並經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep Gold 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(165mg，無，75%)。方法C：3分鐘LRMS[1/2M+1=1005]。1 H NMR(甲醇-d4 )δ：7.97(s,3H),7.17-7.43(m,5H),5.21(s,3H),4.52-4.60(m,12H),4.45(s,2H),4.25(d,J=5.9Hz,3H),4.10(t,J=6.2Hz,3H),3.85-3.93(m,9H),3.71-3.82(m,15H),3.63-3.69(m,6H),3.53-3.62(m,33H),3.48(t,J=6.2Hz,2H),2.27(t,J=7.2Hz,2H),1.74-1.96(m,2H),1.49(s,9H),1.45(s,27H),1.32(s,9H)。A small tube (20 ml) equipped with a stir bar was charged with 4-(decyloxy)-N-{1,3-bis(prop-2-yn-1-yloxy)-2-[(prop-2-yne- 1-yloxy)methyl]propan-2-yl}butanamine (lv-1) (45.0 mg, 0.11 mmol) and [[1S,2R,6R,7R,8S)-1-(13 -azido-2,5,8,11-tetraoxatridec-1-yl)-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0 ~2,6~]undecyl-7-yl]amino acid tert-butyl butyl ester (l-aq-1) (192 mg, 0.361 mmol) of tertiary butanol (3 ml) and water (1.5 ml, go Ionic water) solution. The reaction was purged with nitrogen for 5 minutes and then sodium ascorbate (66.3 mg, 0.328 mmol) was added and a solution of copper (II) sulfate (5.24 mg, 0.0328 mmol) in water (500 ul, deionized water) was added dropwise. . The reaction was allowed to stir at room temperature for 20 hours. After 20 hours, the reaction was cooled to rt and quenched with EtOAc EtOAc (EtOAc) ) Extracted 3 times. The combined organic layers were dried over sodium sulfate and filtered and evaporated. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc EtOAc. Method C: 3 minutes LRMS [1/2 M+1 = 1005]. 1 H NMR (methanol-d 4 ) δ: 7.97 (s, 3H), 7.17-7.43 (m, 5H), 5.21. (s, 3H), 4.52-4.60 (m, 12H), 4.45 (s, 2H), 4.25 (d, J = 5.9 Hz, 3H), 4.10 (t, J = 6.2 Hz, 3H), 3.85 - 3.93 (m, 9H), 3.71-3.82 (m, 15H), 3.63 - 3.69 (m, 6H) , 3.53-3.62 (m, 33H), 3.48 (t, J = 6.2 Hz, 2H), 2.27 (t, J = 7.2 Hz, 2H), 1.74-1.96 (m, 2H), 1.49 (s, 9H), 1.45 (s, 27H), 1.32 (s, 9H).

4-(苄氧基)-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)丁醯胺(63)4-(Benzyloxy)-N-(1,3-bis[(1-S1-[(1S,2R,3R,4R,5S)-4-amino-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-amino-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy Methyl}propan-2-yl)butanamine (63)

令{(1S,2R,6R,7R,8S)-1-[13-(4-{[2-{[4-(苄氧基)丁醯基]胺基}-3-{[1-(1-{(1S,2R,6R,7R,8S)-7-[(三級丁氧羰基)胺基]-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基}-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基]甲氧基}-2-({[1-(1-{(1S,2R,6R,7R,8S)-7-[(三級丁氧羰基)胺基]-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-1-基}-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基]甲氧基}甲基)丙氧基]甲基}-1H-1,2,3-***-1-基)-2,5,8,11-四氧雜十三烷-1-基]-4,4-二甲基-3,5,9,11-四氧雜三環[6.2.1.0~2,6~]十一烷-7-基}胺甲酸三級丁酯(l-ar-1)(150.0mg,0.0747毫莫耳)之乙酸(5ml)、甲醇(1.5ml)及水(1.5ml)溶液經加熱至70℃達18小時。經18小時後，令反應物經冷卻至室溫並經減壓下濃縮。令粗產物經二氯甲烷(10ml)和甲醇(4ml)稀釋並加入4.0M氯化氫之二噁烷溶液(2.0ml,8毫莫耳)。令反應混合物於室溫下經隔夜攪 拌。經18小時後，令反應物於減壓下經濃縮。令粗產物經乙酸乙酯(1ml)稀釋並加入庚烷(10ml)且經減壓下濃縮。隨後將產物置於高真空下達18小時以生成標的化合物(139.0mg,103%)。方法C：3分鐘LRMS[1/2M+1=795]。1 H NMR(甲醇-d4)δ：8.09(s,3H),7.27-7.39(m,5H),5.48(s,3H),4.57-4.66(m,12H),4.47(s,2H),3.98(d,J=9.8Hz,3H),3.90-3.95(m,9H),3.82-3.89(m,6H),3.79(s,6H),3.76(d,J=8.2Hz,3H),3.71(d,J=9.8Hz,3H),3.57-3.69(m,36H),3.50(t,J=6.2Hz,2H),3.21(d,J=9.4Hz,3H),2.29(t,J=7.2Hz,2H),1.85(quin,J=6.8Hz,2H)。Let {(1S,2R,6R,7R,8S)-1-[13-(4-{[2-{[4-(benzyloxy)butanyl)amino}-3-{[1-(1- {(1S,2R,6R,7R,8S)-7-[(tertiary butoxycarbonyl)amino]-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2 .1.0~2,6~]undec-1-yl}-2,5,8,11-tetraoxatridecane-13-yl)-1H-1,2,3-triazole-4- Methoxy]-2-({[1-(1-{(1S,2R,6R,7R,8S)-7-[(tertiarybutoxycarbonyl)amino]-4,4-dimethyl Base-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~]undec-1-yl}-2,5,8,11-tetraoxatridecane-13 -yl)-1H-1,2,3-triazol-4-yl]methoxy}methyl)propoxy]methyl}-1H-1,2,3-triazol-1-yl)- 2,5,8,11-tetraoxatridec-1-yl]-4,4-dimethyl-3,5,9,11-tetraoxatricyclo[6.2.1.0~2,6~ a solution of acetic acid (5 ml), methanol (1.5 ml) and water (1.5 ml) of undecyl-7-yl}amino carboxylic acid tert-butyl ester (1-ar-1) (150.0 mg, 0.0747 mmol) Heat to 70 ° C for 18 hours. After 18 hours the reaction was cooled to rt and concentrated EtOAc. The crude product was diluted with dichloromethane (10 mL) and MeOH (4 mL). The reaction mixture was allowed to stir overnight at room temperature. After 18 hours, the reaction was concentrated under reduced pressure. The crude product was diluted with EtOAc (EtOAc) (EtOAc) The product was then placed under high vacuum for 18 hours to give the title compound (139.0mg, 103%). Method C: 3 minutes LRMS [1/2M + 1 = 795]. 1 H NMR (methanol -d4) δ: 8.09 (s, 3H), 7.27-7.39 (m, 5H), 5.48 (s, 3H), 4.57-4.66 (m, 12H), 4.47 (s, 2H), 3.98 (d, J = 9.8 Hz, 3H), 3.90-3.95 (m, 9H), 3.82-3.89 (m, 6H), 3.79 (s, 6H), 3.76 (d, J = 8.2 Hz, 3H), 3.71 ( d, J = 9.8 Hz, 3H), 3.57-3.69 (m, 36H), 3.50 (t, J = 6.2 Hz, 2H), 3.21 (d, J = 9.4 Hz, 3H), 2.29 (t, J = 7.2) Hz, 2H), 1.85 (quin, J = 6.8 Hz, 2H).

乙酸(1S,2R,3R,4R,5S)-4-(乙醯胺基)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-{[4-(苄氧基)丁醯基]胺基}丙氧基)甲基]-1H-1,2,3-***-1-基}-2,5,8,11-四氧雜十三烷-1-基)-3-(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-2-基酯(l-as-1)Acetic acid (1S, 2R, 3R, 4R, 5S)-4-(acetamido)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R) ,5S)-4-(ethylamino)-2,3-bis(ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R) ,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethoxycarbonyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2 ,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-{[4-(benzyl Oxy)butanyl]amino}propoxy)methyl]-1H-1,2,3-triazol-1-yl}-2,5,8,11-tetraoxatridec-1-yl )-3-(ethoxycarbonyl)-6,8-dioxabicyclo[3.2.1]oct-2-yl ester (l-as-1)

室溫下令4-(苄氧基)-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)丁醯胺(63)(80mg,0.044毫莫耳)溶解於吡啶(無水)(1.5ml,19毫莫耳)並加入乙酸酐(0.125ml,1.33毫莫耳)。隨後令反應物經隔夜加熱至50℃。次晨，令該反應物於減壓下經濃縮。令粗產物經CombiFlash Rf(RediSep Gold 12g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成標的化合物。令該粗標的化合物經CombiFlash Rf(RediSep Gold 4g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成呈膠之標的化合物(54.0mg,62%)。方法C： 1.5分鐘LRMS[1/2M+1=984]。1 H NMR(甲醇-d4 )δ：7.97(s,3H),7.19-7.42(m,5H),5.44(d,J=4.3Hz,3H),5.31(s,3H),5.10(dd,J=10.3,4.1Hz,3H),4.51-4.64(m,12H),4.45(s,2H),4.18(d,J=10.1Hz,3H),3.99(d,J=8.6Hz,3H),3.88(t,J=4.9Hz,6H),3.68-3.82(m,12H),3.52-3.64(m,39H),3.48(t,J=6.2Hz,2H),2.26(t,J=7.4Hz,2H),2.15(s,9H),1.94(d,J=1.2Hz,18H),1.84(t,J=6.8Hz,2H)。4-(Benzyloxy)-N-(1,3-bis[(1-S1-[(1S,2R,3R,4R,5S)-4-amino-2,3-dihydroxy) -6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-three Zin-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-amino-2,3-dihydroxy-6,8- Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl Methoxy]methyl}propan-2-ylbutamine (63) (80 mg, 0.044 mmol) dissolved in pyridine (anhydrous) (1.5 ml, 19 mmol) and added acetic anhydride (0.125 ml) , 1.33 millimoles). The reaction was then allowed to warm to 50 °C overnight. The next morning, the reaction was concentrated under reduced pressure. The crude product was purified via CombiFlash Rf (RediSep Gold 12g cartridge) eluting with 0 to 20% methanol/dichloromethane gradient to afford the title compound. The crude standard compound was purified on a CombiFlash Rf (RediSep Gold 4g cartridge) eluted with 0 to 20% methanol/dichloromethane gradient to afford compound (54.0 mg, 62%). Method C: 1.5 minutes LRMS [1/2M + 1 = 984]. 1 H NMR (methanol-d 4 ) δ: 7.97 (s, 3H), 7.19-7.42 (m, 5H), 5.44 (d, J = 4.3 Hz, 3H), 5.31 (s, 3H), 5.10 (dd, J = 10.3, 4.1 Hz, 3H), 4.51-4.64 (m, 12H), 4.45 (s, 2H), 4.18 (d, J = 10.1 Hz, 3H), 3.99 (d, J = 8.6 Hz, 3H), 3.88 (t, J = 4.9 Hz, 6H), 3.68-3.82 (m, 12H), 3.52-3.64 (m, 39H), 3.48 (t, J = 6.2 Hz, 2H), 2.26 (t, J = 7.4 Hz) , 2H), 2.15 (s, 9H), 1.94 (d, J = 1.2 Hz, 18H), 1.84 (t, J = 6.8 Hz, 2H).

乙酸(1S,2R,3R,4R,5S)-4-(乙醯胺基)-1-{13-[4-({3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-[(4-羥基丁醯基)胺基]丙氧基}甲基)-1H-1,2,3-***-1-基]-2,5,8,11-四氧雜十三烷-1-基}-3-(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-2-基酯(l-at-1)Acetic acid (1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-1-{13-[4-({3-[(1-{1-[(1S,2R,3R,4R) ,5S)-4-(ethylamino)-2,3-bis(ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R) ,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethoxycarbonyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2 ,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-[(4-hydroxybutanyl) Amino]propoxy}methyl)-1H-1,2,3-triazol-1-yl]-2,5,8,11-tetraoxatridecyl-1-yl}-3- (Ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl ester (l-at-1)

令乙酸(1S,2R,3R,4R,5S)-4-(乙醯胺基)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-{[4-(苄氧基)丁醯基]胺基}丙氧基)甲基]-1H-1,2,3-***-1-基}-2,5,8,11-四氧雜十三烷-1-基)-3-(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-2-基酯(l-as-1)(54.0mg,0.027毫莫耳)溶解於甲醇(10.0ml)並令溶液隨後通過H立方體(使用10% Pd/C(小筒)；使用下述參數：溫度：60℃；流速：1.0ml/分鐘；壓力=全部H2 (1大氣壓))。收集溶液並經減壓下濃縮以生成呈膠之標的化合 物(51.0mg,99%)。方法C：3分鐘LRMS[M+Na=1899]。1 H NMR(甲醇-d4 )δ：7.98(s,3H),5.44(d,J=4.3Hz,3H),5.32(s,3H),5.10(dd,J=10.5,3.9Hz,3H),4.41-4.66(m,12H),4.18(d,J=10.5Hz,3H),3.99(d,J=8.6Hz,3H),3.90(t,J=5.1Hz,6H),3.68-3.83(m,12H),3.51-3.67(m,41H),2.24(t,J=7.6Hz,2H),2.15(s,9H),1.94(s,18H),1.69-1.83(m,2H)。Let acetic acid (1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R, 4R,5S)-4-(ethylamino)-2,3-bis(ethoxycarbonyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5, 8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S, 2R,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-1-yl]- 2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-{[4-( Benzyloxy)butanyl]amino}propoxy)methyl]-1H-1,2,3-triazol-1-yl}-2,5,8,11-tetraoxatridecane-1- 3-(Ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl ester (l-as-1) (54.0 mg, 0.027 mmol) dissolved in methanol (10.0 ml) and let the solution pass through the H cube (using 10% Pd/C (small cartridge); use the following parameters: temperature: 60 ° C; flow rate: 1.0 ml/min; pressure = all H 2 (1 atm)) . The solution was collected and concentrated under reduced pressure to give compound (51.0 mg, 99%). Method C: 3 minutes LRMS [M+Na=1899]. 1 H NMR (methanol-d 4 ) δ: 7.98 (s, 3H), 5.44 (d, J = 4.3 Hz, 3H), 5.32 (s, 3H), 5.10 (dd, J = 10.5, 3.9 Hz, 3H) , 4.41-4.66 (m, 12H), 4.18 (d, J = 10.5 Hz, 3H), 3.99 (d, J = 8.6 Hz, 3H), 3.90 (t, J = 5.1 Hz, 6H), 3.68-3.83 ( m, 12H), 3.51-3.67 (m, 41H), 2.24 (t, J = 7.6 Hz, 2H), 2.15 (s, 9H), 1.94 (s, 18H), 1.69-1.83 (m, 2H).

N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-4-羥基丁醯胺(64)N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy Methyl}propan-2-yl)-4-hydroxybutanamine (64)

對乙酸(1S,2R,3R,4R,5S)-4-(乙醯胺基)-1-{13-[4-({3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-[(4-羥基丁醯基)胺基]丙氧基}甲基)-1H-1,2,3-***-1-基]-2,5,8,11-四氧雜十三烷-1-基}-3-(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-2-基酯(l-at-1)(8.5mg,0.0045毫莫耳)之甲醇(1ml)溶液加入0.5M甲氧化鈉之甲醇(0.154ml,0.0770毫莫耳)溶液並令反應物於室溫下經攪拌3小時。經3小時後，令該反應物藉由加入經甲醇輕洗3次之Amberlyst 15離子交換樹脂(CAS#=39389-20-3,RS-106008)中和至pH 5。令反應混合物經過濾並令該樹脂經甲醇輕洗2次。令濾液經減壓下濃縮以生成呈膠之標的化合物(1.5mg,20%)。方法C：3分鐘LRMS[M+45(甲酸)=1668]。1 H NMR(甲醇-d4 )δ：8.00(s,3H),5.21(s,3H),4.53-4.65(m,12H),3.92-4.00(m,6H),3.89(dd,J=11.1,4.9Hz,9H),3.74-3.79(m,9H),3.71(dd,J=9.8,4.3Hz,3H),3.52-3.69(m,44H),2.24(t,J=7.4Hz,2H),1.99(s,9H),1.76(quin,J=6.9Hz,2H)。For acetic acid (1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-1-{13-[4-({3-[(1-{1-[(1S,2R,3R, 4R,5S)-4-(ethylamino)-2,3-bis(ethoxycarbonyl)-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5, 8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S, 2R,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-1-yl]- 2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-[(4-hydroxyl) Butyl) Amino]propoxy}methyl)-1H-1,2,3-triazol-1-yl]-2,5,8,11-tetraoxatridecyl-1-yl}-3 -(Ethyloxy)-6,8-dioxabicyclo[3.2.1]oct-2-yl ester (l-at-1) (8.5 mg, 0.0045 mmol) in methanol (1 ml) A 0.5 M solution of sodium methoxide in methanol (0.154 mL, 0.0770 mmol) was obtained and the mixture was stirred at room temperature for 3 hours. After 3 hours, the reaction was neutralized to pH 5 by adding Amberlyst 15 ion exchange resin (CAS #=39389-20-3, RS-106008) which was lightly washed 3 times with methanol. The reaction mixture was filtered and the resin was washed twice with methanol. The filtrate was concentrated under reduced pressure to give a compound (1.5 mg, 20%). Method C: 3 minutes LRMS [M+45 (carboxylic acid) = 1668]. 1 H NMR (methanol-d 4 ) δ: 8.00 (s, 3H), 5.21. (s, 3H), 4.53-4.65 (m, 12H), 3.92-4.00 (m, 6H), 3.89 (dd, J=11.1) , 4.9 Hz, 9H), 3.74 - 3.79 (m, 9H), 3.71 (dd, J = 9.8, 4.3 Hz, 3H), 3.52-3.69 (m, 44H), 2.24 (t, J = 7.4 Hz, 2H) , 1.99 (s, 9H), 1.76 (quin, J = 6.9 Hz, 2H).

於回流條件下，於適當之溶劑(諸如甲苯)中，藉由使用化合物(I-aw-1)(參閱文獻H.Bruyère et al.,Bioorg.Med.Chem.Lett.,20,2200-2203,(2010))、適當之醇(諸 如化合物(I-an-1))及適當之酸(諸如對甲苯磺酸吡啶鎓)，熟習此技術之人士可合成大抵描述於反應圖3且例示於反應圖4之化合物(66)的原酯連接子以生成化合物(I-ax-1)。於熟習此技術之人士所習知的鹼性條件(諸如催化性碳酸鉀之甲醇溶液)下可進行化合物(I-ax-1)之去保護反應以生成本發明之化合物(65)。可使化合物(65)經進一步官能化以生成本發明所請之其他化合物。因此，於適當之溶劑(諸如N,N-二甲基甲醯胺)中，使用適當之鹼(諸如N,N-二異丙基乙胺)，令化合物(65)與適當之酸和偶合劑(熟習此技術之人士所習知者)或經活化之酯(諸如羥基琥珀醯胺)(諸如化合物(I-s-1))反應可生成化合物(66)。By using the compound (I-aw-1) in a suitable solvent such as toluene under reflux conditions (see H. Bruyère et al., Bioorg. Med. Chem. Lett., 20, 2200-2203). , (2010)), appropriate alcohol (the As the compound (I-an-1)) and a suitable acid (such as pyridinium p-toluenesulfonate), those skilled in the art can synthesize the original of the compound (66) which is generally described in Reaction Scheme 3 and is illustrated in Reaction Scheme 4. The ester linker is used to form a compound (I-ax-1). The deprotection reaction of the compound (I-ax-1) can be carried out under basic conditions (such as a catalytic solution of potassium carbonate in methanol) well known to those skilled in the art to give the compound (65) of the present invention. Compound (65) can be further functionalized to form other compounds of the invention. Thus, in a suitable solvent such as N,N-dimethylformamide, the appropriate base (such as N,N-diisopropylethylamine) is used to give compound (65) with the appropriate acid and The compound (66) can be formed by reacting a mixture (known to those skilled in the art) or an activated ester such as hydroxysuccinimide such as the compound (Is-1).

對1-{[6-(吡啶-2-基二甲硫基)己醯基]氧基}吡咯啶-2,5-二酮(l-s-1)(518mg,2.01毫莫耳)之N,N-二甲基甲醯胺(7ml)溶液加入N-(3-二甲基胺基丙基)-N’-乙基碳二醯亞胺氫氯化物(463mg,2.42毫莫耳)和1-羥基苯並***(326mg,2.42毫莫耳)並於室溫下經攪拌1小時。經1小時後，先後加入2-胺基丙烷-1,3-二醇(183mg,2.01毫莫耳)和N,N-二異丙基乙胺(1.05ml,6.04毫莫耳)。令反應物於室溫下經隔夜攪拌。經18小時後，令該反應物經水稀釋並經二氯甲烷萃取3次。令結合之有機層經鹽水沖洗，置於硫酸鎂上乾燥且經過濾和減壓下濃縮。令粗產物經CombiFlash Rf(RediSep 24g矽膠管柱；經0至20%甲醇/二氯甲烷梯度洗提)純化以生成標的化合物(368mg,55%)。方法C：1.5分鐘LRMS[M+45(甲酸)=375]。1 H NMR(甲醇-d4 )δ：8.38(d,J=4.3Hz,1H),7.84-7.89(m,1H),7.77-7.83(m,1H),7.21(t,J=5.7Hz,1H),3.92(quin,J=5.5Hz,1H),3.51-3.70(m,4H),2.82(t,J=7.2Hz,2H),2.21(t,J=7.4Hz,2H),1.71(quin,J=7.3Hz,2H),1.60(quin,J=7.5Hz,2H),1.37-1.51(m,2H)。N for 1-{[6-(pyridin-2-yldimethylthio)hexanyl]oxy}pyrrolidine-2,5-dione (ls-1) (518 mg, 2.01 mmol), N-dimethylformamide (7 ml) solution was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (463 mg, 2.42 mmol) and 1 Hydroxybenzotriazole (326 mg, 2.42 mmol) and stirred at room temperature for 1 hour. After 1 hour, 2-aminopropane-1,3-diol (183 mg, 2.01 mmol) and N,N-diisopropylethylamine (1.05 ml, 6.04 mmol) were added. The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and extracted with dichloromethane three times. The combined organic layers were washed with brine, dried over magnesium sulfate and filtered and evaporated. The crude product was purified on a CombiFlash Rf (EtOAc EtOAc EtOAc. Method C: 1.5 minutes LRMS [M+45 (carboxylic acid) = 375]. 1 H NMR (methanol-d 4 ) δ: 8.38 (d, J = 4.3 Hz, 1H), 7.84-7.89 (m, 1H), 7.77-7.83 (m, 1H), 7.21. (t, J = 5.7 Hz, 1H), 3.92 (quin, J=5.5 Hz, 1H), 3.51-3.70 (m, 4H), 2.82 (t, J = 7.2 Hz, 2H), 2.21 (t, J = 7.4 Hz, 2H), 1.71 ( Quin, J = 7.3 Hz, 2H), 1.60 (quin, J = 7.5 Hz, 2H), 1.37-1.51 (m, 2H).

N-(2-甲氧基-1,3-二噁烷-5-基)-6-(吡啶-2-基二甲硫基)己醯胺(l-av-1)N-(2-methoxy-1,3-dioxan-5-yl)-6-(pyridin-2-yldimethylthio)hexylamine (l-av-1)

對N-(1,3-二羥基丙-2-基)-6-(吡啶-2-基二甲硫基)己醯胺(l-au-1)(280mg,0.847毫莫耳)之二氯甲烷(0.605ml)和原甲酸三甲酯(0.5ml,5毫莫耳)之混合物加入對甲苯磺酸一水合物(1.78mg,0.00847毫莫耳)。令反應物於室溫下經攪拌3小時。經3小時後，TLC顯示起始物幾乎完全耗盡。令反應物經二氯甲烷稀釋並經飽和碳酸氫鈉水溶液(3×1ml)和鹽水(1ml)沖洗，置於無水碳酸鉀上乾燥且經過濾和減壓下濃縮以生成粗標的化合物(263.0mg,83.3%)。方法C：3分鐘模式(基本模式：管柱：基本：Waters Acquity UPLC BEH,2.1mm×50mm,C18,1.8μm；移動相：A：0.1%氨水(v/v)；B：0.1%氨之乙腈溶液(v/v))。LRMS[M+45=417]。順式/反式異構物之1：1混合物：異構物1：1 H NMR(甲醇-d4 )δ：8.41(d,J=4.7Hz,1H),7.86-7.92(m,1H),7.80-7.86(m,1H),7.20-7.27(m,1H),5.31(s,1H),4.29(d,J=2.7Hz,1H),3.92-3.96(m,1H),3.83(br.s.,1H),3.63(d,J=5.1Hz,1H),3.59(dd,J=11.5,3.7Hz,1H),3.42(s,3H),2.85(t,J=7.2Hz,2H),2.21-2.30(m,2H),1.68-1.80(m,2H),l.56-1.67(m,2H),1.39-1.53(m,2H)；異構物2：1 H NMR(甲醇-d4 )δ：8.41(d,J=4.7Hz, 1H),7.86-7.92(m,1H),7.80-7.86(m,1H),7.20-7.27(m,1H),5.27(s,1H),4.26(d,J=2.7Hz,1H),3.92-3.96(m,2H),3.86-3.91(m,1H),3.59(dd,J=11.5,3.7Hz,1H),3.38(s,3H),2.85(t,J=7.2Hz,2H),2.21-2.30(m,2H),1.68-1.80(m,2H),1.56-1.67(m,2H),1.39-1.53(m,2H)。For N-(1,3-dihydroxypropan-2-yl)-6-(pyridin-2-yldimethylthio)hexylamine (l-au-1) (280 mg, 0.847 mmol) A mixture of methyl chloride (0.605 ml) and trimethyl orthoformate (0.5 ml, 5 mmol) was added to p-toluenesulfonic acid monohydrate (1.78 mg, 0.00847 mmol). The reaction was allowed to stir at room temperature for 3 hours. After 3 hours, TLC showed the starting material was almost completely consumed. The reaction was diluted with EtOAc (EtOAc) (EtOAc m. , 83.3%). Method C: 3 minute mode (basic mode: column: basic: Waters Acquity UPLC BEH, 2.1 mm x 50 mm, C18, 1.8 μm; mobile phase: A: 0.1% ammonia (v/v); B: 0.1% ammonia Acetonitrile solution (v/v)). LRMS [M+45=417]. 1:1 mixture of cis/trans isomers: isomer 1: 1 H NMR (methanol-d 4 ) δ: 8.41 (d, J = 4.7 Hz, 1H), 7.86-7.92 (m, 1H) , 7.80-7.86 (m, 1H), 7.20-7.27 (m, 1H), 5.31 (s, 1H), 4.29 (d, J = 2.7 Hz, 1H), 3.92-3.96 (m, 1H), 3.83 (br .s., 1H), 3.63 (d, J = 5.1 Hz, 1H), 3.59 (dd, J = 11.5, 3.7 Hz, 1H), 3.42 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H) ), 2.21-2.30 (m, 2H), 1.68-1.80 (m, 2H), 1.56-1.67 (m, 2H), 1.39-1.53 (m, 2H); isomer 2: 1 H NMR (methanol) -d 4 ) δ: 8.41 (d, J = 4.7 Hz, 1H), 7.86-7.92 (m, 1H), 7.80-7.86 (m, 1H), 7.20-7.27 (m, 1H), 5.27 (s, 1H) ), 4.26 (d, J = 2.7 Hz, 1H), 3.92-3.96 (m, 2H), 3.86-3.91 (m, 1H), 3.59 (dd, J = 11.5, 3.7 Hz, 1H), 3.38 (s, 3H), 2.85 (t, J = 7.2 Hz, 2H), 2.21-2.30 (m, 2H), 1.68-1.80 (m, 2H), 1.56-1.67 (m, 2H), 1.39-1.53 (m, 2H) .

藥理數據Pharmacological data

藉由於一或多種下述之功能性分析的活性，可證實使用本發明之化合物可實施本發明所描述的治療經導向去唾液酸糖蛋白受體(ASGPR)所調節之疾病。供應來源記載於括號內。By virtue of the activity of one or more of the functional assays described below, it can be demonstrated that the use of the compounds of the invention can be used to treat the diseases modulated by the targeted asialoglycoprotein receptor (ASGPR) described herein. The source of supply is recorded in brackets.

表面電漿共振測量Surface plasma resonance measurement 製備經生物素化之ASGPR：Preparation of biotinylated ASGPR:

野生型ASGPr H1於大腸桿菌中經表現呈不溶之包涵體(IB)。令細胞沉降物再懸浮於TBS緩衝液pH 8.0(其含有0.1mg/ml溶菌酶+25μg/ml DNase+10μg/ml RNase+10mM MgCl2 )且於冰上經攪拌直至充分摻合。令混合物通過微流化器2次並於30,000 x g下經離心30分鐘。令所生成之IB沉降物經TBS緩衝液(pH 8.0)+3M脲沖洗並經離心且此程序經水再重複3次。令該IB沉降物溶解於10mM Tris+8M脲+100mM β-巰乙醇(pH 8.5)並經攪拌約20分鐘且隨後經離心以丟棄任何沉澱物。對於下述之操作，“緩衝液T”係指20mM Tris+0.5M NaCl+25mM CaCl2 。令上清液經緩衝液T+2mM β-巰乙醇+8M脲(pH 8.0)稀釋成約0.5mg/ml並隨後於4℃下隔夜經8至10倍過量體積之緩衝液T+2mM β-巰乙醇+2M脲(pH 8.0)透析。於4℃下且於緩衝液T+1mM β-巰乙醇+1M脲(pH 8.0)中重複透析約24小時，其中數次體積更換，且藉由緩衝液T+5mM GSH+1mM GSSG(pH 7.5)進行最終透析，其中3次體積更換。令所生成之樣品經離心並將上清液載入經N-乙醯基-D-半乳糖胺瓊脂堆疊之Pharmacia XK 26管柱，其係經緩衝液T+2mM TCEP(pH 8.0)平衡。令該管柱經該緩衝液沖洗直至再建立基礎值。令結合之蛋白經20mM Tris+0.5M NaCl+2mM TCEP+2mM EDTA(pH 8.0)洗提。自大腸桿菌細胞沉降物(5L；70wgm)，最終產率約50mg。Wild-type ASGPr H1 is expressed as an insoluble inclusion body (IB) in E. coli. The cell sediment was resuspended in TBS buffer pH 8.0 (which contained 0.1 mg/ml lysozyme + 25 μg/ml DNase + 10 μg/ml RNase + 10 mM MgCl 2 ) and stirred on ice until fully blended. The mixture was passed through a microfluidizer 2 times and centrifuged at 30,000 xg for 30 minutes. The resulting IB sediment was rinsed with TBS buffer (pH 8.0) + 3 M urea and centrifuged and the procedure was repeated three more times with water. The IB sediment was dissolved in 10 mM Tris + 8 M urea + 100 mM β-indole ethanol (pH 8.5) and stirred for about 20 minutes and then centrifuged to discard any precipitate. For the following procedure, "buffer T" refers to 20 mM Tris + 0.5 M NaCl + 25 mM CaCl 2 . The supernatant was diluted to about 0.5 mg/ml with buffer T+2 mM β-巯 ethanol + 8 M urea (pH 8.0) and then 8 to 10 times excess volume of buffer T + 2 mM β-巯 at 4 ° C overnight. Dialysis with ethanol + 2 M urea (pH 8.0). The dialysis was repeated at 4 ° C in buffer T+1 mM β-巯 ethanol + 1 M urea (pH 8.0) for about 24 hours, several volumes were replaced, and buffer T + 5 mM GSH + 1 mM GSSG (pH 7.5) The final dialysis was performed with 3 volume changes. The resulting sample was centrifuged and the supernatant was loaded onto a Pharmacia XK 26 column of N-acetyl-D-galactosamine agar stack, which was equilibrated with buffer T + 2 mM TCEP (pH 8.0). The column is flushed through the buffer until a base value is established. The bound protein was eluted with 20 mM Tris + 0.5 M NaCl + 2 mM TCEP + 2 mM EDTA (pH 8.0). From E. coli cell sediment (5 L; 70 wgm), the final yield was approximately 50 mg.

雖然BSA有一個未形成二硫鍵之半胱胺酸(Cys34)，但是此硫醇基通常經小硫醇(諸如半胱胺酸)阻斷而呈混合之二硫化物或經好氧氧化作用而呈次磺酸。經發現於多種測試方法中，二硫化物還原或標記係用於使ASGPR結合結構域衍生化之最不含雜質的方法。選擇溫和之二硫化物還原條件以使埋藏之內股(溶劑不能接近者)交聯不受破壞。因此，立即於生物素化之前，令該ASGPR樣品首先經1mM TCEP培育以確定該樣品含有單一自由硫醇。令該蛋白於4℃下隔夜與19倍莫耳過量之Pierce順丁烯二醯亞胺-PEG2-生物素試劑的PBS溶液反應。Although BSA has a cysteine (Cys34) that does not form a disulfide bond, this thiol group is usually blocked by a small thiol (such as cysteine) to form a mixed disulfide or aerobic oxidation. It is sulfenic acid. Among the various test methods found, disulfide reduction or labeling is the most impurity-free method for derivatizing the ASGPR binding domain. Mild disulfide reduction conditions are selected to crosslink the buried inner strands (solvent inaccessible) without damage. Therefore, immediately prior to biotinylation, the ASGPR sample was first incubated with 1 mM TCEP to determine that the sample contained a single free thiol. The protein was reacted overnight at 4 ° C with a 19-fold molar excess of Pierce maleimide-PEG2-biotin reagent in PBS.

使用PD-10管柱(GE Healthcare)或Zeba旋轉脫鹽管 柱(Thermo/Pierce)並依據製造商之方法，除去該樣品內過量之生物素。該產物之LC-MS分析驗證存在單一質量，其含有添加與該順丁烯二醯亞胺加成物之分子量一致的525amu。因TCEP係通過該順丁烯二醯亞胺反應存在，若該蛋白業已經完全還原(使其他半胱胺酸硫醇存在)，則結果將會是含有多種加成物之異質產物及經除去關鍵之結構二硫連結之可能的錯誤摺疊或沉澱。未觀察到此等結果。進一步，觀察到之標準結合專一性(GalNAc/甲基半乳糖苷/乳糖)強烈地建議：SPR載片上之足夠的蛋白係經適當地摺疊和顯現。Use PD-10 column (GE Healthcare) or Zeba rotary desalination tube The column (Thermo/Pierce) and the excess biotin in the sample was removed according to the manufacturer's method. LC-MS analysis of this product confirmed the presence of a single mass containing 525 amu which was consistent with the molecular weight of the maleimide adduct. Since TCEP is present by the maleimide reaction, if the protein has been completely reduced (the other cysteine thiol is present), the result will be a heterogeneous product containing multiple adducts and removed. The key structural disulfide linkage may be misfolded or precipitated. No such results were observed. Further, the standard binding specificity observed (GalNAc/methylgalactoside/lactose) strongly suggests that sufficient protein on the SPR slide is properly folded and visualized.

SPR結合測量SPR combined measurement

使用Biacore 3000(GE Healthcare)且於25℃下進行化合物之所有SPR測量。藉由SA感測器晶片(GE Healthcare)或一般感測器晶片，使用抗生物素蛋白Neutravidin(Pierce Biochemical；其藉由標準胺偶合於CM5感測器晶片(GE Healthcare)而被固定化)，一般於2000至3000共振單位(Ru)下使經生物素化之ASGPR固定化。流洗緩衝液係HBS(10mM HEPES,150mM NaCl)、20mM CaCl2 、0.01% p20、3% DMSO、或50mM Tris、150mM NaCl,50mM CaCl2 、0.01% p20、3% DMSO pH 7.5。化合物經流洗緩衝液稀釋成濃度900uM且經3倍系列稀釋至3.7uM。對每個濃度皆經2重複，注入化合物溶液(50ul/分鐘經1分鐘)並隨後經1分鐘解離。對多體共 軛物(二體、三體)，令該等共軛物經流洗緩衝液稀釋至濃度100nM或10nM並經系列稀釋。注入該等共軛物達2分鐘並偵測截止速率達300或600秒。經截止期數據完成後，注入900uM GalNAc以替代該等化合物而使該受體表面返回自由態。使用Scrubber2(Biologic Software,Inc.)處理所有數據以對準零位、並列、對照及校正以排除體積效果。對Scrubber2中該等化合物和單一共軛之分子，藉由擬合穩態結合反應以測定KD 值。顯現動力學反應之多體共軛物的KD 值係經Scrubber2處理且擬合於BiaEval(GE Healthcare)以取得開始和截止速率參數，藉以計算KD 值。由多個實驗之數值反應標準誤差。All SPR measurements of the compounds were performed using a Biacore 3000 (GE Healthcare) at 25 °C. Using avidin wafer (GE Healthcare) or a general sensor wafer, avidin Neutravidin (Pierce Biochemical; which was immobilized by standard amine coupling to a CM5 sensor wafer (GE Healthcare)), The biotinylated ASGPR is typically immobilized at 2000 to 3000 resonance units (Ru). The flow wash buffer was HBS (10 mM HEPES, 150 mM NaCl), 20 mM CaCl 2 , 0.01% p20, 3% DMSO, or 50 mM Tris, 150 mM NaCl, 50 mM CaCl 2 , 0.01% p20, 3% DMSO pH 7.5. The compound was diluted to a concentration of 900 uM in serial wash buffer and serially diluted to 3.7 uM in 3 fold. For each concentration, 2 repetitions were made, and the compound solution (50 ul/min for 1 minute) was injected and then dissociated over 1 minute. For multibody conjugates (dimer, trisomy), the conjugates were diluted to a concentration of 100 nM or 10 nM in serial wash buffer and serially diluted. The conjugates were injected for 2 minutes and the cut-off rate was detected for 300 or 600 seconds. Upon completion of the deadline data, 900 uM GalNAc was injected to replace the compounds to return the receptor surface to a free state. All data was processed using Scrubber 2 (Biologic Software, Inc.) to align zero, side by side, control and correction to exclude volume effects. The compounds of Scrubber2 molecular conjugate of single and, by fitting the measured K D value to the steady-state binding reaction. K D values show kinetics of the reaction system as much as conjugate body was processed and fitted in Scrubber2 BiaEval (GE Healthcare) to obtain the rate of start and end parameters, thereby calculating K D values. The standard error is reflected by the values of multiple experiments.

得到下述之SPR結合分析的結果，其中每次實驗被各別報告或註記實驗數(n)和標準誤差。The results of the SPR binding assay described below were obtained, with each experiment being individually reported or annotated with the number of experiments (n) and standard error.

本發明之說明書參照多種文獻。該等文獻之揭露基於所有目的全部併入本申請案作為參考。The description of the present invention refers to various documents. The disclosure of such documents is hereby incorporated by reference in its entirety for all its purposes.

熟習此技術之人士當能瞭解：在未偏離本發明之範圍或精神下，可對本發明作多種修飾和變化。考量說明書和實施本發明，熟習此技術之人士當能瞭解本發明之其他實施態樣。包括實施例之本案的說明書應當被視為僅是例示性，本發明之真實範圍和精神係示於下述之申請專利範圍。It will be appreciated by those skilled in the art that various modifications and changes can be made in the present invention without departing from the scope of the invention. Other embodiments of the invention will be apparent to those skilled in the art in the <RTIgt; The description of the present invention, including the examples, is to be considered as illustrative only, and the true scope and spirit of the invention are shown in the following claims.

<110> 輝瑞股份有限公司<110> Pfizer Inc.

<120> 作為去唾液酸糖蛋白受體(ASGPR)導向劑之經取代-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二醇化合物<120> Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compound as a salivary glycoprotein receptor (ASGPR) directing agent

<140> TW 104115586<140> TW 104115586

<141> 2015-05-15<141> 2015-05-15

<150> US 62/000,211<150> US 62/000,211

<151> 2014-05-19<151> 2014-05-19

<150> US 62/001,540<150> US 62/001,540

<151> 2014-05-21<151> 2014-05-21

<150> US 62/139,254<150> US 62/139,254

<151> 2015-03-27<151> 2015-03-27

<160> 847<160> 847

<170> PatentIn版本3.5<170> PatentIn version 3.5

<210> 1<210> 1

<211> 1056<211> 1056

<212> PRT<212> PRT

<213> 敗血性巴氏桿菌<213> Pasteurella septicum

<400> 1 <400> 1

<210> 2<210> 2

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 2 <400> 2

<210> 3<210> 3

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 無毒李斯特菌<213> Atomic Listeria

<400> 3 <400> 3

<210> 4<210> 4

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 4 <400> 4

<210> 5<210> 5

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 5 <400> 5

<210> 6<210> 6

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 6 <400> 6

<210> 7<210> 7

<211> 1377<211> 1377

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 7 <400> 7

<210> 8<210> 8

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 8 <400> 8

<210> 9<210> 9

<211> 131<211> 131

<212> PRT<212> PRT

<213> 肝螺桿菌<213> Hepatic Helicobacter

<400> 9 <400> 9

<210> 10<210> 10

<211> 1059<211> 1059

<212> PRT<212> PRT

<213> 產琥珀酸沃廉菌<213> Producing succinic acid

<400> 10 <400> 10

<210> 11<210> 11

<211> 1409<211> 1409

<212> PRT<212> PRT

<213> 產琥珀酸沃廉菌<213> Producing succinic acid

<400> 11 <400> 11

<210> 12<210> 12

<211> 1374<211> 1374

<212> PRT<212> PRT

<213> 核棱桿菌<213> Nuclear bacillus

<400> 12 <400> 12

<210> 13<210> 13

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 白喉桿菌<213> Diphtheria

<400> 13 <400> 13

<210> 14<210> 14

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 14 <400> 14

<210> 15<210> 15

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 15 <400> 15

<210> 16<210> 16

<211> 1236<211> 1236

<212> PRT<212> PRT

<213> 運動黴漿菌<213> Sports Mycoplasma

<400> 16 <400> 16

<210> 17<210> 17

<211> 1372<211> 1372

<212> PRT<212> PRT

<213> 退伍軍人嗜肺病菌<213> Veterans of Pneumoconiosis

<400> 17 <400> 17

<210> 18<210> 18

<211> 1122<211> 1122

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 18 <400> 18

<210> 19<210> 19

<211> 1128<211> 1128

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 19 <400> 19

<210> 20<210> 20

<211> 1123<211> 1123

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 20 <400> 20

<210> 21<210> 21

<211> 1436<211> 1436

<212> PRT<212> PRT

<213> 脆弱類桿菌<213> Bacteroides fragilis

<400> 21 <400> 21

<210> 22<210> 22

<211> 1314<211> 1314

<212> PRT<212> PRT

<213> 滑膜黴漿菌<213> Synovial fungus

<400> 22 <400> 22

<210> 23<210> 23

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 23 <400> 23

<210> 24<210> 24

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 24 <400> 24

<210> 25<210> 25

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 25 <400> 25

<210> 26<210> 26

<211> 1173<211> 1173

<212> PRT<212> PRT

<213> 深紅紅螺菌<213> Rhodospirillum

<400> 26 <400> 26

<210> 27<210> 27

<211> 997<211> 997

<212> PRT<212> PRT

<213> 嗜鹼異單胞菌<213> Alkalophilic Alcaligenes

<400> 27 <400> 27

<210> 28<210> 28

<211> 1027<211> 1027

<212> PRT<212> PRT

<213> 海洋芽殖小小梨形菌<213> Marine Budding Small Pear

<400> 28 <400> 28

<210> 29<210> 29

<211> 158<211> 158

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 29 <400> 29

<210> 30<210> 30

<211> 393<211> 393

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 30 <400> 30

<210> 31<210> 31

<211> 1066<211> 1066

<212> PRT<212> PRT

<213> 沼澤紅假單胞菌<213> Rhodopseudomonas palustris

<400> 31 <400> 31

<210> 32<210> 32

<211> 1149<211> 1149

<212> PRT<212> PRT

<213> 唾液乳酸桿菌<213> Lactobacillus saliva

<400> 32 <400> 32

<210> 33<210> 33

<211> 1064<211> 1064

<212> PRT<212> PRT

<213> 沼澤紅假單胞菌<213> Rhodopseudomonas palustris

<400> 33 <400> 33

<210> 34<210> 34

<211> 1166<211> 1166

<212> PRT<212> PRT

<213> 漢堡硝化菌<213> Hamburg Nitrifying Bacteria

<400> 34 <400> 34

<210> 35<210> 35

<211> 641<211> 641

<212> PRT<212> PRT

<213> 漢堡硝化菌<213> Hamburg Nitrifying Bacteria

<400> 35 <400> 35

<210> 36<210> 36

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 36 <400> 36

<210> 37<210> 37

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 37 <400> 37

<210> 38<210> 38

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 38 <400> 38

<210> 39<210> 39

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 39 <400> 39

<210> 40<210> 40

<211> 1121<211> 1121

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 40 <400> 40

<210> 41<210> 41

<211> 1388<211> 1388

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 41 <400> 41

<210> 42<210> 42

<211> 1138<211> 1138

<212> PRT<212> PRT

<213> 解纖維熱酸菌<213> Fibrinolytic bacteria

<400> 42 <400> 42

<210> 43<210> 43

<211> 1629<211> 1629

<212> PRT<212> PRT

<213> 新兒手法朗西斯菌<213> Newborns Francis

<400> 43 <400> 43

<210> 44<210> 44

<211> 1068<211> 1068

<212> PRT<212> PRT

<213> 烯解變磷桿菌<213> Alcoholism

<400> 44 <400> 44

<210> 45<210> 45

<211> 1125<211> 1125

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 45 <400> 45

<210> 46<210> 46

<211> 1064<211> 1064

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 慢生根瘤菌BTAil<223> Slow-growing Rhizobium BTAil

<400> 46 <400> 46

<210> 47<210> 47

<211> 1354<211> 1354

<212> PRT<212> PRT

<213> 嗜冷黃桿菌<213> Pneumovirus

<400> 47 <400> 47

<210> 48<210> 48

<211> 1062<211> 1062

<212> PRT<212> PRT

<213> 琥珀酸放線桿菌<213> Actinobacillus succinogenes

<400> 48 <400> 48

<210> 49<210> 49

<211> 1340<211> 1340

<212> PRT<212> PRT

<213> 恒河猴腸道菌<213> Rhesus monkey intestinal bacteria

<400> 49 <400> 49

<210> 50<210> 50

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 50 <400> 50

<210> 51<210> 51

<211> 1037<211> 1037

<212> PRT<212> PRT

<213> 丁香通菌<213> Clove fungus

<400> 51 <400> 51

<210> 52<210> 52

<211> 1107<211> 1107

<212> PRT<212> PRT

<213> 凸腹真菌<213> Condylar fungus

<400> 52 <400> 52

<210> 53<210> 53

<211> 1136<211> 1136

<212> PRT<212> PRT

<213> 戈登鏈球菌<213> Streptococcus gordon

<400> 53 <400> 53

<210> 54<210> 54

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 54 <400> 54

<210> 55<210> 55

<211> 1079<211> 1079

<212> PRT<212> PRT

<213> 恒雄芝氏溝鞭藻玫瑰桿菌<213> Rhesus Brassica

<400> 55 <400> 55

<210> 56<210> 56

<211> 1096<211> 1096

<212> PRT<212> PRT

<213> 長真菌<213> Long fungus

<400> 56 <400> 56

<210> 57<210> 57

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 57 <400> 57

<210> 58<210> 58

<211> 1050<211> 1050

<212> PRT<212> PRT

<213> 重氮營養葡糖酸醋桿菌<213> Diazo nutrition Acetobacter gluconate

<400> 58 <400> 58

<210> 59<210> 59

<211> 1391<211> 1391

<212> PRT<212> PRT

<213> 溶藻菌<213> Algae

<400> 59 <400> 59

<210> 60<210> 60

<211> 1116<211> 1116

<212> PRT<212> PRT

<213> 螺狀梭菌<213> Clostridium

<400> 60 <400> 60

<210> 61<210> 61

<211> 1348<211> 1348

<212> PRT<212> PRT

<213> 大分哥德爾菌<213> Oita G.

<400> 61 <400> 61

<210> 62<210> 62

<211> 1129<211> 1129

<212> PRT<212> PRT

<213> 嬰兒鏈球菌<213> Streptococcus streptococci

<400> 62 <400> 62

<210> 63<210> 63

<211> 1065<211> 1065

<212> PRT<212> PRT

<213> 產氣夾膜梭菌<213> Clostridium perfringens

<400> 63 <400> 63

<210> 64<210> 64

<211> 1195<211> 1195

<212> PRT<212> PRT

<213> 小亞歷山大菌<213> Little Alexander

<400> 64 <400> 64

<210> 65<210> 65

<211> 1101<211> 1101

<212> PRT<212> PRT

<213> 嗜黏蛋白阿克曼菌<213> Amygdalin

<400> 65 <400> 65

<210> 66<210> 66

<211> 1187<211> 1187

<212> PRT<212> PRT

<213> 長雙歧桿菌<213> Bifidobacterium longum

<400> 66 <400> 66

<210> 67<210> 67

<211> 166<211> 166

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 未經培養之白蟻群1細菌群Rs-D17<223> Uncultivated termite colony 1 bacterial group Rs-D17

<400> 67 <400> 67

<210> 68<210> 68

<211> 1032<211> 1032

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 未經培養之白蟻群1細菌群Rs-D17<223> Uncultivated termite colony 1 bacterial group Rs-D17

<400> 68 <400> 68

<210> 69<210> 69

<211> 1032<211> 1032

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 未經培養之白蟻群1細菌群Rs-D17<223> Uncultivated termite colony 1 bacterial group Rs-D17

<400> 69 <400> 69

<210> 70<210> 70

<211> 1361<211> 1361

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 70 <400> 70

<210> 71<210> 71

<211> 1348<211> 1348

<212> PRT<212> PRT

<213> 馬鏈球菌<213> Streptococcus equi

<400> 71 <400> 71

<210> 72<210> 72

<211> 1341<211> 1341

<212> PRT<212> PRT

<213> 酸奶瘤胃球菌<213> Yogurt rumen bacteria

<400> 72 <400> 72

<210> 73<210> 73

<211> 1003<211> 1003

<212> PRT<212> PRT

<213> 重氮營養葡糖酸醋桿菌<213> Diazo nutrition Acetobacter gluconate

<400> 73 <400> 73

<210> 74<210> 74

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 74 <400> 74

<210> 75<210> 75

<211> 1504<211> 1504

<212> PRT<212> PRT

<213> 擬類桿菌<213> Bacteroides

<400> 75 <400> 75

<210> 76<210> 76

<211> 1426<211> 1426

<212> PRT<212> PRT

<213> 生痰二氧化碳嗜纖維菌<213> 痰 痰 carbon dioxide fibrin

<400> 76 <400> 76

<210> 77<210> 77

<211> 1443<211> 1443

<212> PRT<212> PRT

<213> 強生氏副類桿菌<213> Paragonimus

<400> 77 <400> 77

<210> 78<210> 78

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 78 <400> 78

<210> 79<210> 79

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 79 <400> 79

<210> 80<210> 80

<211> 1021<211> 1021

<212> PRT<212> PRT

<213> 解纖維梭菌<213> Clostridium cellulosum

<400> 80 <400> 80

<210> 81<210> 81

<211> 1131<211> 1131

<212> PRT<212> PRT

<213> 艾氏食酸菌<213> E. faecalis

<400> 81 <400> 81

<210> 82<210> 82

<211> 1122<211> 1122

<212> PRT<212> PRT

<213> 豬鏈球菌<213> Streptococcus suis

<400> 82 <400> 82

<210> 83<210> 83

<211> 1509<211> 1509

<212> PRT<212> PRT

<213> 嗜糞類桿菌<213> Bacillus

<400> 83 <400> 83

<210> 84<210> 84

<211> 1219<211> 1219

<212> PRT<212> PRT

<213> 解纖維素類桿菌<213> Cellulolytic bacteria

<400> 84 <400> 84

<210> 85<210> 85

<211> 1329<211> 1329

<212> PRT<212> PRT

<213> 三普卡尼菌<213> Tricainia

<400> 85 <400> 85

<210> 86<210> 86

<211> 1152<211> 1152

<212> PRT<212> PRT

<213> 衣林凡羅斯菌<213> Rhodospirillum

<400> 86 <400> 86

<210> 87<210> 87

<211> 686<211> 686

<212> PRT<212> PRT

<213> 陪伴糞球菌<213> Accompaniment

<400> 87 <400> 87

<210> 88<210> 88

<211> 1105<211> 1105

<212> PRT<212> PRT

<213> 環犬放線菌<213> Actinomyces

<400> 88 <400> 88

<210> 89<210> 89

<211> 1361<211> 1361

<212> PRT<212> PRT

<213> 四環厭氧球菌<213> Four-ring Anaerococci

<400> 89 <400> 89

<210> 90<210> 90

<211> 1377<211> 1377

<212> PRT<212> PRT

<213> 短乳酸桿菌<213> Lactobacillus brevis

<400> 90 <400> 90

<210> 91<210> 91

<211> 1239<211> 1239

<212> PRT<212> PRT

<213> 布氏乳酸桿菌<213> Lactobacillus bulgaricus

<400> 91 <400> 91

<210> 92<210> 92

<211> 1381<211> 1381

<212> PRT<212> PRT

<213> 醱酵乳酸桿菌<213> Lactobacillus fermentum

<400> 92 <400> 92

<210> 93<210> 93

<211> 1306<211> 1306

<212> PRT<212> PRT

<213> 食神鞘氨醇桿菌<213> Sphingomonas

<400> 93 <400> 93

<210> 94<210> 94

<211> 1358<211> 1358

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 胺基酸球菌D21<223> Amino acid bacteria D21

<400> 94 <400> 94

<210> 95<210> 95

<211> 653<211> 653

<212> PRT<212> PRT

<213> 鼻痘菌<213> Nasecta

<400> 95 <400> 95

<210> 96<210> 96

<211> 1436<211> 1436

<212> PRT<212> PRT

<213> 牙齦二氧化碳嗜纖維菌<213> gingival carbon dioxide fibrin

<400> 96 <400> 96

<210> 97<210> 97

<211> 1069<211> 1069

<212> PRT<212> PRT

<213> 臘狀桿菌<213> Flavonoids

<400> 97 <400> 97

<210> 98<210> 98

<211> 1391<211> 1391

<212> PRT<212> PRT

<213> 詹氏乳酸桿菌<213> Lactobacillus japonicus

<400> 98 <400> 98

<210> 99<210> 99

<211> 1114<211> 1114

<212> PRT<212> PRT

<213> 直腸真菌<213> Rectal fungus

<400> 99 <400> 99

<210> 100<210> 100

<211> 1362<211> 1362

<212> PRT<212> PRT

<213> 副酪蛋白乳酸桿菌<213> Lactobacillus paracasei

<400> 100 <400> 100

<210> 101<210> 101

<211> 1056<211> 1056

<212> PRT<212> PRT

<213> 小放線桿菌<213> Actinobacteria

<400> 101 <400> 101

<210> 102<210> 102

<211> 1081<211> 1081

<212> PRT<212> PRT

<213> 淺黃色奈瑟菌<213> Neisseria

<400> 102 <400> 102

<210> 103<210> 103

<211> 1392<211> 1392

<212> PRT<212> PRT

<213> 溶血李生球菌<213> Hemolytic bacterium

<400> 103 <400> 103

<210> 104<210> 104

<211> 702<211> 702

<212> PRT<212> PRT

<213> 胃腸炎螺桿菌<213> Gastroenteritis Helicobacter

<400> 104 <400> 104

<210> 105<210> 105

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 壞乳鏈球菌<213> Streptococcus faecalis

<400> 105 <400> 105

<210> 106<210> 106

<211> 1007<211> 1007

<212> PRT<212> PRT

<213> 加拿大螺桿菌<213> Canadian Helicobacter

<400> 106 <400> 106

<210> 107<210> 107

<211> 1397<211> 1397

<212> PRT<212> PRT

<213>γ 變形菌N4-7<213> γ- proteobacteria N4-7

<400> 107 <400> 107

<210> 108<210> 108

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 108 <400> 108

<210> 109<210> 109

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 109 <400> 109

<210> 110<210> 110

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 110 <400> 110

<210> 111<210> 111

<211> 1426<211> 1426

<212> PRT<212> PRT

<213> 黃褐二氧化碳嗜纖維菌<213> Yellow-Brown Carbon Dioxide

<400> 111 <400> 111

<210> 112<210> 112

<211> 1424<211> 1424

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 副類桿菌D13<223> Parabacterium bacillus D13

<400> 112 <400> 112

<210> 113<210> 113

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 詹氏乳酸桿菌<213> Lactobacillus japonicus

<400> 113 <400> 113

<210> 114<210> 114

<211> 1140<211> 1140

<212> PRT<212> PRT

<213> 腸羅斯菌<213> Rhizobacteria

<400> 114 <400> 114

<210> 115<210> 115

<211> 992<211> 992

<212> PRT<212> PRT

<213> 文氏密螺旋體<213> Helicobacter burgdorferi

<400> 115 <400> 115

<210> 116<210> 116

<211> 1340<211> 1340

<212> PRT<212> PRT

<213> 屎腸球菌<213> Enterococcus faecium

<400> 116 <400> 116

<210> 117<210> 117

<211> 1363<211> 1363

<212> PRT<212> PRT

<213> 鼠李糖乳酸桿菌<213> Lactobacillus rhamnosus

<400> 117 <400> 117

<210> 118<210> 118

<211> 1234<211> 1234

<212> PRT<212> PRT

<213> 坦納氏普雷沃氏菌<213> Prevotella tanarius

<400> 118 <400> 118

<210> 119<210> 119

<211> 1496<211> 1496

<212> PRT<212> PRT

<213> 真口普雷沃氏菌<213> Prevotella

<400> 119 <400> 119

<210> 120<210> 120

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 灰色奈瑟菌<213> Neisseria

<400> 120 <400> 120

<210> 121<210> 121

<211> 1512<211> 1512

<212> PRT<212> PRT

<213> 琥珀酸纖維菌<213> Succinic acid bacteria

<400> 121 <400> 121

<210> 122<210> 122

<211> 1259<211> 1259

<212> PRT<212> PRT

<213> 念珠狀鏈桿菌<213> Streptomyces faecalis

<400> 122 <400> 122

<210> 123<210> 123

<211> 1091<211> 1091

<212> PRT<212> PRT

<213> 羞怯動彎桿菌<213> Shame bacillus

<400> 123 <400> 123

<210> 124<210> 124

<211> 872<211> 872

<212> PRT<212> PRT

<213> 巴氏卡拉菌<213> Carrageen

<400> 124 <400> 124

<210> 125<210> 125

<211> 1229<211> 1229

<212> PRT<212> PRT

<213> 乳酸片球菌<213> Pediococcus lactis

<400> 125 <400> 125

<210> 126<210> 126

<211> 1398<211> 1398

<212> PRT<212> PRT

<213> 極小韋永氏球菌<213> Very small Wyoming

<400> 126 <400> 126

<210> 127<210> 127

<211> 1485<211> 1485

<212> PRT<212> PRT

<213> 二路普雷沃氏菌<213> Two-way Prevotella

<400> 127 <400> 127

<210> 128<210> 128

<211> 1218<211> 1218

<212> PRT<212> PRT

<213> 口頰普雷沃氏菌<213> P. vivax

<400> 128 <400> 128

<210> 129<210> 129

<211> 1218<211> 1218

<212> PRT<212> PRT

<213> 替莫普雷沃氏菌<213> T. viva

<400> 129 <400> 129

<210> 130<210> 130

<211> 1487<211> 1487

<212> PRT<212> PRT

<213> 替莫普雷沃氏菌<213> T. viva

<400> 130 <400> 130

<210> 131<210> 131

<211> 1138<211> 1138

<212> PRT<212> PRT

<213> 齒雙歧桿菌<213> Bifidobacterium dentate

<400> 131 <400> 131

<210> 132<210> 132

<211> 587<211> 587

<212> PRT<212> PRT

<213> 微黃奈瑟菌<213> Neisseria

<400> 132 <400> 132

<210> 133<210> 133

<211> 1269<211> 1269

<212> PRT<212> PRT

<213> 雞敗血性黴漿菌<213> Chicken septicum

<400> 133 <400> 133

<210> 134<210> 134

<211> 1354<211> 1354

<212> PRT<212> PRT

<213> 產黑普雷沃氏菌<213> Prevotella

<400> 134 <400> 134

<210> 135<210> 135

<211> 1130<211> 1130

<212> PRT<212> PRT

<213> 解沒食子酸鏈球菌<213> Streptomyces gallis

<400> 135 <400> 135

<210> 136<210> 136

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 解沒食子酸鏈球菌<213> Streptomyces gallis

<400> 136 <400> 136

<210> 137<210> 137

<211> 1168<211> 1168

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 固氮螺菌B510<223> Azospirillum B510

<400> 137 <400> 137

<210> 138<210> 138

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 138 <400> 138

<210> 139<210> 139

<211> 1024<211> 1024

<212> PRT<212> PRT

<213> 鼬螺桿菌<213> Helicobacter pylori

<400> 139 <400> 139

<210> 140<210> 140

<211> 765<211> 765

<212> PRT<212> PRT

<213> 溶纖維丁酸弧菌<213> Vibrio solani

<400> 140 <400> 140

<210> 141<210> 141

<211> 1338<211> 1338

<212> PRT<212> PRT

<213> 靈巧糞球菌<213> Phytophthora

<400> 141 <400> 141

<210> 142<210> 142

<211> 1035<211> 1035

<212> PRT<212> PRT

<213> 布氏卡拉菌<213> K. brucei

<400> 142 <400> 142

<210> 143<210> 143

<211> 1270<211> 1270

<212> PRT<212> PRT

<213> 雞敗血性黴漿菌<213> Chicken septicum

<400> 143 <400> 143

<210> 144<210> 144

<211> 1204<211> 1204

<212> PRT<212> PRT

<213> 瘤胃普雷沃氏菌<213> Rudolococcus rumen

<400> 144 <400> 144

<210> 145<210> 145

<211> 1178<211> 1178

<212> PRT<212> PRT

<213> 印氏史卡都菌<213> S. berghei

<400> 145 <400> 145

<210> 146<210> 146

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 派氏葛拉菌<213> Gramella

<400> 146 <400> 146

<210> 147<210> 147

<211> 1388<211> 1388

<212> PRT<212> PRT

<213> 深海王衣菌<213> King sea bacillus

<400> 147 <400> 147

<210> 148<210> 148

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 甲烷氧化菌<213> Methane oxidizing bacteria

<400> 148 <400> 148

<210> 149<210> 149

<211> 1186<211> 1186

<212> PRT<212> PRT

<213> ***加德納菌<213> Gardnerella vaginalis

<400> 149 <400> 149

<210> 150<210> 150

<211> 1434<211> 1434

<212> PRT<212> PRT

<213> 牙齦普林單胞菌<213> P. gingivalis

<400> 150 <400> 150

<210> 151<210> 151

<211> 1341<211> 1341

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 嗜？菌口腔型386株F0131<223> Addiction? Bacterial oral type 386 strain F0131

<400> 151 <400> 151

<210> 152<210> 152

<211> 1391<211> 1391

<212> PRT<212> PRT

<213> 加氏乳酸桿菌<213> Lactobacillus

<400> 152 <400> 152

<210> 153<210> 153

<211> 1426<211> 1426

<212> PRT<212> PRT

<213> 食神鞘氨醇桿菌<213> Sphingomonas

<400> 153 <400> 153

<210> 154<210> 154

<211> 1361<211> 1361

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 154 <400> 154

<210> 155<210> 155

<211> 1436<211> 1436

<212> PRT<212> PRT

<213> 脆弱類桿菌<213> Bacteroides fragilis

<400> 155 <400> 155

<210> 156<210> 156

<211> 1517<211> 1517

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 類桿菌20 3<223> Bacteroides 20 3

<400> 156 <400> 156

<210> 157<210> 157

<211> 1399<211> 1399

<212> PRT<212> PRT

<213> 口歐菌<213> Oryzae

<400> 157 <400> 157

<210> 158<210> 158

<211> 1398<211> 1398

<212> PRT<212> PRT

<213> 非典韋永氏球菌<213> SARS

<400> 158 <400> 158

<210> 159<210> 159

<211> 795<211> 795

<212> PRT<212> PRT

<213> 解糖？普雷沃氏菌<213> Sugar? Prevo

<400> 159 <400> 159

<210> 160<210> 160

<211> 1428<211> 1428

<212> PRT<212> PRT

<213> 伯克氏菌<213> Burkholderia

<400> 160 <400> 160

<210> 161<210> 161

<211> 1025<211> 1025

<212> PRT<212> PRT

<213> γ變形菌N4-7<213> γ-proteobacteria N4-7

<400> 161 <400> 161

<210> 162<210> 162

<211> 1364<211> 1364

<212> PRT<212> PRT

<213> 乳酸片球菌<213> Pediococcus lactis

<400> 162 <400> 162

<210> 163<210> 163

<211> 1364<211> 1364

<212> PRT<212> PRT

<213> 牙嗜？菌<213> Dental addiction? bacteria

<400> 163 <400> 163

<210> 164<210> 164

<211> 1089<211> 1089

<212> PRT<212> PRT

<213> 馬氏棒狀桿菌<213> Corynebacterium marxianus

<400> 164 <400> 164

<210> 165<210> 165

<211> 1134<211> 1134

<212> PRT<212> PRT

<213> 和緩鏈球菌<213> Streptococcus mutans

<400> 165 <400> 165

<210> 166<210> 166

<211> 1373<211> 1373

<212> PRT<212> PRT

<213> 牛鏈球菌<213> Streptococcus bovis

<400> 166 <400> 166

<210> 167<210> 167

<211> 1099<211> 1099

<212> PRT<212> PRT

<213> 擁擠棒狀桿菌<213> Crowded Corynebacterium

<400> 167 <400> 167

<210> 168<210> 168

<211> 1054<211> 1054

<212> PRT<212> PRT

<213> 胸膜肺炎放線桿菌<213> Actinobacillus pleuropneumoniae

<400> 168 <400> 168

<210> 169<210> 169

<211> 1369<211> 1369

<212> PRT<212> PRT

<213> 惰性乳酸桿菌<213> Lactobacillus inertia

<400> 169 <400> 169

<210> 170<210> 170

<211> 1420<211> 1420

<212> PRT<212> PRT

<213> 兩叉雙歧桿菌<213> Bifidobacterium bifidum

<400> 170 <400> 170

<210> 171<210> 171

<211> 1092<211> 1092

<212> PRT<212> PRT

<213> 營養泥桿菌<213> Nutrient

<400> 171 <400> 171

<210> 172<210> 172

<211> 994<211> 994

<212> PRT<212> PRT

<213> 唐氏鏈球菌<213> Streptococcus faecalis

<400> 172 <400> 172

<210> 173<210> 173

<211> 1052<211> 1052

<212> PRT<212> PRT

<213> 普氏胺菌<213> Plasmodium

<400> 173 <400> 173

<210> 174<210> 174

<211> 1023<211> 1023

<212> PRT<212> PRT

<213> 淫亂螺桿菌<213> Fornicaria Helicobacter

<400> 174 <400> 174

<210> 175<210> 175

<211> 874<211> 874

<212> PRT<212> PRT

<213> 西利堅李斯特菌<213> Listeria monocytogenes

<400> 175 <400> 175

<210> 176<210> 176

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 淋病奈瑟菌<213> Neisseria gonorrhoeae

<400> 176 <400> 176

<210> 177<210> 177

<21> 1326<21> 1326

<212> PRT<212> PRT

<213> 假刺鏈球菌<213> S. sphaericus

<400> 177 <400> 177

<210> 178<210> 178

<211> 1150<211> 1150

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 178 <400> 178

<210> 179<210> 179

<211> 1150<211> 1150

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 179 <400> 179

<210> 180<210> 180

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 咽峽炎鏈球菌<213> Streptococcus angina

<400> 180 <400> 180

<210> 181<210> 181

<211> 849<211> 849

<212> PRT<212> PRT

<213> 綿羊李斯特菌<213> Listeria monocytogenes

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (780)..(780)<222> (780)..(780)

<223> Xaa可為任何天然存在之胺基酸<223> Xaa can be any naturally occurring amino acid

<400> 181 <400> 181

<210> 182<210> 182

<211> 1457<211> 1457

<212> PRT<212> PRT

<213> 頰普雷沃氏菌<213> P. vivax

<400> 182 <400> 182

<210> 183<210> 183

<211> 1330<211> 1330

<212> PRT<212> PRT

<213> 義大利腸球菌<213> Italian Enterococcus

<400> 183 <400> 183

<210> 184<210> 184

<211> 1123<211> 1123

<212> PRT<212> PRT

<213> 彎曲動彎桿菌<213> B. benthamella

<400> 184 <400> 184

<210> 185<210> 185

<211> 1054<211> 1054

<212> PRT<212> PRT

<213> 路鄧葡萄球菌<213> Staphylococcus aureus

<400> 185 <400> 185

<210> 186<210> 186

<211> 586<211> 586

<212> PRT<212> PRT

<213> 解乳酸假胺菌<213> Solution to pseudo-ammonium lactate

<400> 186 <400> 186

<210> 187<210> 187

<211> 1385<211> 1385

<212> PRT<212> PRT

<213> 麻疹孿生球菌<213> Measles Mycobacterium

<400> 187 <400> 187

<210> 188<210> 188

<211> 1029<211> 1029

<212> PRT<212> PRT

<213> 脫氮嗜脂菌<213> Denitrifying lipophilic bacteria

<400> 188 <400> 188

<210> 189<210> 189

<211> 1422<211> 1422

<212> PRT<212> PRT

<213> 華德薩特菌<213> Waldstatella

<400> 189 <400> 189

<210> 190<210> 190

<211> 1132<211> 1132

<212> PRT<212> PRT

<213> 薩特硝菌<213> Sutter Nitrobacter

<400> 190 <400> 190

<210> 191<210> 191

<211> 1327<211> 1327

<212> PRT<212> PRT

<213> 口臭單菌<213> Bad breath single bacteria

<400> 191 <400> 191

<210> 192<210> 192

<211> 738<211> 738

<212> PRT<212> PRT

<213> 食果膠密螺旋體<213> Pectin

<400> 192 <400> 192

<210> 193<210> 193

<211> 1377<211> 1377

<212> PRT<212> PRT

<213> 馬鏈球菌<213> Streptococcus equi

<400> 193 <400> 193

<210> 194<210> 194

<211> 1128<211> 1128

<212> PRT<212> PRT

<213> 前庭鏈球菌<213> vestibular streptococci

<400> 194 <400> 194

<210> 195<210> 195

<211> 1080<211> 1080

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 解甲烷菌ATCC 49242<223> Methanogens ATCC 49242

<400> 195 <400> 195

<210> 196<210> 196

<211> 1087<211> 1087

<212> PRT<212> PRT

<213> 琥珀酸派菌<213> Succinic acid bacteria

<400> 196 <400> 196

<210> 197<210> 197

<211> 1375<211> 1375

<212> PRT<212> PRT

<213> 瘤胃乳酸桿菌<213> Lactobacillus rumen

<400> 197 <400> 197

<210> 198<210> 198

<211> 1391<211> 1391

<212> PRT<212> PRT

<213> 口普雷沃氏菌<213> Prevotella

<400> 198 <400> 198

<210> 199<210> 199

<211> 1167<211> 1167

<212> PRT<212> PRT

<213> 犬鏈球菌<213> Streptococcus canis

<400> 199 <400> 199

<210> 200<210> 200

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 金黃色葡萄球菌<213> Staphylococcus aureus

<400> 200 <400> 200

<210> 201<210> 201

<211> 1156<211> 1156

<212> PRT<212> PRT

<213> 白色瘤胃球菌<213> White rumen cocci

<400> 201 <400> 201

<210> 202<210> 202

<211> 1440<211> 1440

<212> PRT<212> PRT

<213> 有毒威克斯菌<213> Toxic Wix

<400> 202 <400> 202

<210> 203<210> 203

<211> 1179<211> 1179

<212> PRT<212> PRT

<213> 球螺旋體<213> Spherical

<400> 203 <400> 203

<210> 204<210> 204

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 解沒食子酸鏈球菌<213> Streptomyces gallis

<400> 204 <400> 204

<210> 205<210> 205

<211> 1044<211> 1044

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 亞硝酸細菌AL212<223> nitrous acid bacteria AL212

<400> 205 <400> 205

<210> 206<210> 206

<211> 1045<211> 1045

<212> PRT<212> PRT

<213> 蝴蝶蘭細菌性褐斑病菌<213> Phalaenopsis bacterial brown spot disease

<400> 206 <400> 206

<210> 207<210> 207

<211> 1218<211> 1218

<212> PRT<212> PRT

<213> 西牙普雷沃氏菌<213> Prevotella falciparum

<400> 207 <400> 207

<210> 208<210> 208

<211> 1458<211> 1458

<212> PRT<212> PRT

<213> 單氏黃菌<213> Flavobacterium

<400> 208 <400> 208

<210> 209<210> 209

<211> 1384<211> 1384

<212> PRT<212> PRT

<213> 科里氏桿菌<213> Coriolis

<400> 209 <400> 209

<210> 210<210> 210

<211> 1077<211> 1077

<212> PRT<212> PRT

<213> 巴爾奈瑟菌<213> Barnesella

<400> 210 <400> 210

<210> 211<210> 211

<211> 1029<211> 1029

<212> PRT<212> PRT

<213> 脫氮嗜脂菌<213> Denitrifying lipophilic bacteria

<400> 211 <400> 211

<210> 212<210> 212

<211> 1122<211> 1122

<212> PRT<212> PRT

<213> 豬鏈球菌<213> Streptococcus suis

<400> 212 <400> 212

<210> 213<210> 213

<211> 1428<211> 1428

<212> PRT<212> PRT

<213> 運動副華德薩特菌<213> Sports Deputy Waldstadt

<400> 213 <400> 213

<210> 214<210> 214

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 布氏乳酸桿菌<213> Lactobacillus bulgaricus

<400> 214 <400> 214

<210> 215<210> 215

<211> 1090<211> 1090

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鞘脂單胞菌S17<223> Sphingomonas S17

<400> 215 <400> 215

<210> 216<210> 216

<211> 1000<211> 1000

<212> PRT<212> PRT

<213> 金格桿菌<213> G. gingivalis

<400> 216 <400> 216

<210> 217<210> 217

<211> 1130<211> 1130

<212> PRT<212> PRT

<213> 巴氏鏈球菌<213> Streptococcus mutans

<400> 217 <400> 217

<210> 218<210> 218

<211> 1119<211> 1119

<212> PRT<212> PRT

<213> 棒狀乳酸桿菌<213> Lactobacillus

<400> 218 <400> 218

<210> 219<210> 219

<211> 1126<211> 1126

<212> PRT<212> PRT

<213> 香腸乳酸桿菌<213> Lactobacillus

<400> 219 <400> 219

<210> 220<210> 220

<211> 1380<211> 1380

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 艾格氏菌YY7918<223> Ehrella YY7918

<400> 220 <400> 220

<210> 221<210> 221

<211> 1430<211> 1430

<212> PRT<212> PRT

<213> 犬咬二氧化碳嗜纖維菌<213> Dog bites carbon dioxide fibrin

<400> 221 <400> 221

<210> 222<210> 222

<211> 1348<211> 1348

<212> PRT<212> PRT

<213> 大分哥德爾菌<213> Oita G.

<400> 222 <400> 222

<210> 223<210> 223

<211> 1352<211> 1352

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 巨球形菌UPII 135-E<223> Megagonium UPII 135-E

<400> 223 <400> 223

<210> 224<210> 224

<211> 650<211> 650

<212> PRT<212> PRT

<213> 普氏嗜血桿菌<213> Haemophilus

<400> 224 <400> 224

<210> 225<210> 225

<211> 1062<211> 1062

<212> PRT<212> PRT

<213> 鈴木變形菌<213> Suzuki Proteus

<400> 225 <400> 225

<210> 226<210> 226

<211> 1052<211> 1052

<212> PRT<212> PRT

<213> 副流感嗜血桿菌<213> Haemophilus parainfluenzae

<400> 226 <400> 226

<210> 227<210> 227

<211> 1331<211> 1331

<212> PRT<212> PRT

<213> 舊金山乳酸桿菌<213> Lactobacillus San Francisco

<400> 227 <400> 227

<210> 228<210> 228

<211> 1473<211> 1473

<212> PRT<212> PRT

<213> 嗜鰓黃桿菌<213> Flavobacterium

<400> 228 <400> 228

<210> 229<210> 229

<211> 933<211> 933

<212> PRT<212> PRT

<213> 衣阿華黴漿菌<213> Iowa mold

<400> 229 <400> 229

<210> 230<210> 230

<211> 1358<211> 1358

<212> PRT<212> PRT

<213> 腸胺基酸球菌<213> Enterococci

<400> 230 <400> 230

<210> 231<210> 231

<211> 983<211> 983

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 231 <400> 231

<210> 232<210> 232

<211> 1338<211> 1338

<212> PRT<212> PRT

<213> 獼猴鏈球菌<213> Rhesus rhesus

<400> 232 <400> 232

<210> 233<210> 233

<211> 1265<211> 1265

<212> PRT<212> PRT

<213> 綿羊肺炎黴漿菌<213> Sheep Pneumoniae

<400> 233 <400> 233

<210> 234<210> 234

<211> 1535<211> 1535

<212> PRT<212> PRT

<213> 柱狀黃桿菌<213> Flavobacterium columnar

<400> 234 <400> 234

<210> 235<210> 235

<211> 1459<211> 1459

<212> PRT<212> PRT

<213> 柱狀黃桿菌<213> Flavobacterium columnar

<400> 235 <400> 235

<210> 236<210> 236

<211> 1389<211> 1389

<212> PRT<212> PRT

<213> 變形酒球菌<213> Deformed bacterium

<400> 236 <400> 236

<210> 237<210> 237

<211> 1425<211> 1425

<212> PRT<212> PRT

<213> 昏普雷沃氏菌<213> Prevotella

<400> 237 <400> 237

<210> 238<210> 238

<211> 1473<211> 1473

<212> PRT<212> PRT

<213> 梭狀凍？樣桿菌<213> Shuttle frozen? Bacillus

<400> 238 <400> 238

<210> 239<210> 239

<211> 1365<211> 1365

<212> PRT<212> PRT

<213> 齦溝產線菌<213> 龈 产 产

<400> 239 <400> 239

<210> 240<210> 240

<211> 1130<211> 1130

<212> PRT<212> PRT

<213> 馬其頓鏈球菌<213> Macedonia streptococci

<400> 240 <400> 240

<210> 241<210> 241

<211> 1367<211> 1367

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 241 <400> 241

<210> 242<210> 242

<211> 1233<211> 1233

<212> PRT<212> PRT

<213> 犬黴漿菌<213> Canine mold

<400> 242 <400> 242

<210> 243<210> 243

<211> 1375<211> 1375

<212> PRT<212> PRT

<213> 強生氏乳酸桿菌<213> Lactobacillus johnsonii

<400> 243 <400> 243

<210> 244<210> 244

<211> 1053<211> 1053

<212> PRT<212> PRT

<213> 金黃葡萄球菌<213> Staphylococcus aureus

<400> 244 <400> 244

<210> 245<210> 245

<211> 1063<211> 1063

<212> PRT<212> PRT

<213> 米氏西蒙斯菌<213> Simmons

<400> 245 <400> 245

<210> 246<210> 246

<211> 1509<211> 1509

<212> PRT<212> PRT

<213> 扭曲冷彎曲菌<213> Twisted cold Campylobacter

<400> 246 <400> 246

<210> 247<210> 247

<211> 1112<211> 1112

<212> PRT<212> PRT

<213> 模仿葡萄球菌<213> Mimics Staphylococcus

<400> 247 <400> 247

<210> 248<210> 248

<211> 1274<211> 1274

<212> PRT<212> PRT

<213> 雞敗血性黴漿菌<213> Chicken septicum

<400> 248 <400> 248

<210> 249<210> 249

<211> 1122<211> 1122

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 249 <400> 249

<210> 250<210> 250

<211> 1236<211> 1236

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 250 <400> 250

<210> 251<210> 251

<211> 1059<211> 1059

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 251 <400> 251

<210> 252<210> 252

<211> 1166<211> 1166

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 252 <400> 252

<210> 253<210> 253

<211> 1149<211> 1149

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 253 <400> 253

<210> 254<210> 254

<211> 1314<211> 1314

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 254 <400> 254

<210> 255<210> 255

<211> 1064<211> 1064

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 255 <400> 255

<210> 256<210> 256

<211> 1401<211> 1401

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 256 <400> 256

<210> 257<210> 257

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 257 <400> 257

<210> 258<210> 258

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 258 <400> 258

<210> 259<210> 259

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 259 <400> 259

<210> 260<210> 260

<211> 15<211> 15

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 260 <400> 260

<210> 261<210> 261

<211> 8<211> 8

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 261 <400> 261

<210> 262<210> 262

<211> 27<211> 27

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 262 <400> 262

<210> 263<210> 263

<211> 8<211> 8

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之胺基酸序列<223> Synthetic amino acid sequence

<400> 263 <400> 263

<210> 264<210> 264

<211> 240<211> 240

<212> PRT<212> PRT

<213> 乙酸菌<213> Acetate

<400> 264 <400> 264

<210> 265<210> 265

<211> 400<211> 400

<212> PRT<212> PRT

<213> 乙酸菌<213> Acetate

<400> 265 <400> 265

<210> 266<210> 266

<211> 376<211> 376

<212> PRT<212> PRT

<213> 乙酸菌<213> Acetate

<400> 266 <400> 266

<210> 267<210> 267

<211> 1054<211> 1054

<212> PRT<212> PRT

<213> 豬放線桿菌<213> Actinobacillus

<400> 267 <400> 267

<210> 268<210> 268

<211> 239<211> 239

<212> PRT<212> PRT

<213> 尿放線桿菌<213> Actinobacillus urtica

<400> 268 <400> 268

<210> 269<210> 269

<211> 400<211> 400

<212> PRT<212> PRT

<213> 尿放線桿菌<213> Actinobacillus urtica

<400> 269 <400> 269

<210> 270<210> 270

<211> 1113<211> 1113

<212> PRT<212> PRT

<213> 喬格放線菌<213> Acta Phytophthora

<400> 270 <400> 270

<210> 271<210> 271

<211> 1101<211> 1101

<212> PRT<212> PRT

<213> 內氏放線菌<213> Actinomyces

<400> 271 <400> 271

<210> 272<210> 272

<211> 1181<211> 1181

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 放線菌口腔型180株F0310<223> Actinomycetes oral type 180 strain F0310

<400> 272 <400> 272

<210> 273<210> 273

<211> 1120<211> 1120

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 放線菌口腔型848株F0332<223> Actinomycetes oral type 848 strain F0332

<400> 273 <400> 273

<210> 274<210> 274

<211> 1095<211> 1095

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 放線菌口腔型175株F0384<223> Actinomycetes oral type 175 strains F0384

<400> 274 <400> 274

<210> 275<210> 275

<211> 1144<211> 1144

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 放線菌ICM47<223> Actinomycetes ICM47

<400> 275 <400> 275

<210> 276<210> 276

<211> 1103<211> 1103

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 放線菌口腔型181株F0379<223> Actinomycetes oral type 181 strains F0379

<400> 276 <400> 276

<210> 277<210> 277

<211> 1114<211> 1114

<212> PRT<212> PRT

<213> 圖列茨放線菌<213> Actinomyces

<400> 277 <400> 277

<210> 278<210> 278

<211> 1113<211> 1113

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 烷烴降解菌W11-5<223> Alkane Degrading Bacteria W11-5

<400> 278 <400> 278

<210> 279<210> 279

<211> 1146<211> 1146

<212> PRT<212> PRT

<213> 脂環酸芽孢桿菌<213> Alicyclobacillus

<400> 279 <400> 279

<210> 280<210> 280

<211> 1552<211> 1552

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 厭氧噬菌HS1<223> Anaerobic phage HS1

<400> 280 <400> 280

<210> 281<210> 281

<211> 1515<211> 1515

<212> PRT<212> PRT

<213> 嗜熱厭氧噬菌<213> Thermophilic anaerobic bacteriophages

<400> 281 <400> 281

<210> 282<210> 282

<211> 333<211> 333

<212> PRT<212> PRT

<213> 臘狀桿菌<213> Flavonoids

<400> 282 <400> 282

<210> 283<210> 283

<211> 1068<211> 1068

<212> PRT<212> PRT

<213> 臘狀桿菌<213> Flavonoids

<400> 283 <400> 283

<210> 284<210> 284

<211> 1078<211> 1078

<212> PRT<212> PRT

<213> 臘狀桿菌<213> Flavonoids

<400> 284 <400> 284

<210> 285<210> 285

<211> 1088<211> 1088

<212> PRT<212> PRT

<213> 史密氏芽孢桿菌<213> Bacillus smithii

<400> 285 <400> 285

<210> 286<210> 286

<211> 1069<211> 1069

<212> PRT<212> PRT

<213> 蘇力菌<213> Suri

<400> 286 <400> 286

<210> 287<210> 287

<211> 206<211> 206

<212> PRT<212> PRT

<213> 解纖維素類桿菌<213> Cellulolytic bacteria

<400> 287 <400> 287

<210> 288<210> 288

<211> 349<211> 349

<212> PRT<212> PRT

<213> 糞類桿菌<213> Fecal bacillus

<400> 288 <400> 288

<210> 289<210> 289

<211> 1504<211> 1504

<212> PRT<212> PRT

<213> 糞類桿菌<213> Fecal bacillus

<400> 289 <400> 289

<210> 290<210> 290

<211> 1509<211> 1509

<212> PRT<212> PRT

<213> 埃氏類桿菌<213> Escherichia coli

<400> 290 <400> 290

<210> 291<210> 291

<211> 1526<211> 1526

<212> PRT<212> PRT

<213> 糞便類桿菌<213> Fecal bacteria

<400> 291 <400> 291

<210> 292<210> 292

<211> 1509<211> 1509

<212> PRT<212> PRT

<213> 流類桿菌<213> Bacillus

<400> 292 <400> 292

<210> 293<210> 293

<211> 1436<211> 1436

<212> PRT<212> PRT

<213> 脆弱類桿菌<213> Bacteroides fragilis

<400> 293 <400> 293

<210> 294<210> 294

<211> 1512<211> 1512

<212> PRT<212> PRT

<213> 諾氏類桿菌<213> Bacillus

<400> 294 <400> 294

<210> 295<210> 295

<211> 779<211> 779

<212> PRT<212> PRT

<213> 油類桿菌<213> Oily bacillus

<400> 295 <400> 295

<210> 296<210> 296

<211> 653<211> 653

<212> PRT<212> PRT

<213> 油類桿菌<213> Oily bacillus

<400> 296 <400> 296

<210> 297<210> 297

<211> 1436<211> 1436

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 類桿菌D2<223> Bacteroides D2

<400> 297 <400> 297

<210> 298<210> 298

<211> 1510<211> 1510

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 類桿菌D2<223> Bacteroides D2

<400> 298 <400> 298

<210> 299<210> 299

<211> 1436<211> 1436

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 類桿菌2_1_16<223> Bacteroides 2_1_16

<400> 299 <400> 299

<210> 300<210> 300

<211> 1424<211> 1424

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 類桿菌3_1_19<223> Bacteroides 3_1_19

<400> 300 <400> 300

<210> 301<210> 301

<211> 1055<211> 1055

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 類桿菌3_1_33FAA<223> Bacteroides 3_1_33FAA

<400> 301 <400> 301

<210> 302<210> 302

<211> 1055<211> 1055

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 類桿菌9_1_42FAA<223> Bacteroides 9_1_42FAA

<400> 302 <400> 302

<210> 303<210> 303

<211> 286<211> 286

<212> PRT<212> PRT

<213> 單形類桿菌<213> Bacteroides monocytogenes

<400> 303 <400> 303

<210> 304<210> 304

<211> 1508<211> 1508

<212> PRT<212> PRT

<213> 單形類桿菌<213> Bacteroides monocytogenes

<400> 304 <400> 304

<210> 305<210> 305

<211> 1210<211> 1210

<212> PRT<212> PRT

<213> 單形類桿菌<213> Bacteroides monocytogenes

<400> 305 <400> 305

<210> 306<210> 306

<211> 1504<211> 1504

<212> PRT<212> PRT

<213> 普通類桿菌<213> Common Bacillus

<400> 306 <400> 306

<210> 307<210> 307

<211> 1153<211> 1153

<212> PRT<212> PRT

<213> 大鼠腸道擬桿菌<213> Rat intestinal bacillus

<400> 307 <400> 307

<210> 308<210> 308

<211> 1352<211> 1352

<212> PRT<212> PRT

<213> 巴特類桿菌<213> B. bacillus

<400> 308 <400> 308

<210> 309<210> 309

<211> 1415<211> 1415

<212> PRT<212> PRT

<213> 動物潰瘍伯格菌<213> Animal ulcers

<400> 309 <400> 309

<210> 310<210> 310

<211> 1430<211> 1430

<212> PRT<212> PRT

<213> 動物潰瘍伯格菌<213> Animal ulcers

<400> 310 <400> 310

<210> 311<210> 311

<211> 1281<211> 1281

<212> PRT<212> PRT

<213> 兩叉雙歧桿菌<213> Bifidobacterium bifidum

<400> 311 <400> 311

<210> 312<210> 312

<211> 1121<211> 1121

<212> PRT<212> PRT

<213> 齒雙歧桿菌<213> Bifidobacterium dentate

<400> 312 <400> 312

<210> 313<210> 313

<211> 354<211> 354

<212> PRT<212> PRT

<213> 長雙歧桿菌<213> Bifidobacterium longum

<400> 313 <400> 313

<210> 314<210> 314

<211> 1124<211> 1124

<212> PRT<212> PRT

<213> 長雙歧桿菌<213> Bifidobacterium longum

<400> 314 <400> 314

<210> 315<210> 315

<211> 166<211> 166

<212> PRT<212> PRT

<213> 長雙歧桿菌<213> Bifidobacterium longum

<400> 315 <400> 315

<210> 316<210> 316

<211> 1138<211> 1138

<212> PRT<212> PRT

<213> 長雙歧桿菌<213> Bifidobacterium longum

<400> 316 <400> 316

<210> 317<210> 317

<211> 182<211> 182

<212> PRT<212> PRT

<213> 長雙歧桿菌<213> Bifidobacterium longum

<400> 317 <400> 317

<210> 318<210> 318

<211> 441<211> 441

<212> PRT<212> PRT

<213> 長雙歧桿菌<213> Bifidobacterium longum

<400> 318 <400> 318

<210> 319<210> 319

<211> 967<211> 967

<212> PRT<212> PRT

<213> 長雙歧桿菌<213> Bifidobacterium longum

<400> 319 <400> 319

<210> 320<210> 320

<211> 1151<211> 1151

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 雙歧桿菌12_1_47BFAA<223> Bifidobacterium 12_1_47BFAA

<400> 320 <400> 320

<210> 321<210> 321

<211> 1092<211> 1092

<212> PRT<212> PRT

<213> 側胞短芽胞桿菌<213> Bacillus sphaericus

<400> 321 <400> 321

<210> 322<210> 322

<211> 103<211> 103

<212> PRT<212> PRT

<213> 溶纖維丁酸弧菌<213> Vibrio solani

<400> 322 <400> 322

<210> 323<210> 323

<211> 177<211> 177

<212> PRT<212> PRT

<213> 溶纖維丁酸弧菌<213> Vibrio solani

<400> 323 <400> 323

<210> 324<210> 324

<211> 1442<211> 1442

<212> PRT<212> PRT

<213> 沙氏源洋菌<213> Sharks

<400> 324 <400> 324

<210> 325<210> 325

<211> 984<211> 984

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 325 <400> 325

<210> 326<210> 326

<211> 984<211> 984

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 326 <400> 326

<210> 327<210> 327

<211> 984<211> 984

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 327 <400> 327

<210> 328<210> 328

<211> 984<211> 984

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 328 <400> 328

<210> 329<210> 329

<211> 987<211> 987

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 329 <400> 329

<210> 330<210> 330

<211> 984<211> 984

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 330 <400> 330

<210> 331<210> 331

<211> 987<211> 987

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 331 <400> 331

<210> 332<210> 332

<211> 984<211> 984

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 332 <400> 332

<210> 333<210> 333

<211> 965<211> 965

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 333 <400> 333

<210> 334<210> 334

<211> 965<211> 965

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 334 <400> 334

<210> 335<210> 335

<211> 965<211> 965

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 335 <400> 335

<210> 336<210> 336

<211> 933<211> 933

<212> PRT<212> PRT

<213> 大腸彎曲桿菌<213> Campylobacter coli

<400> 336 <400> 336

<210> 337<210> 337

<211> 666<211> 666

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 337 <400> 337

<210> 338<210> 338

<211> 190<211> 190

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 338 <400> 338

<210> 339<210> 339

<211> 985<211> 985

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 339 <400> 339

<210> 340<210> 340

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 340 <400> 340

<210> 341<210> 341

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 341 <400> 341

<210> 342<210> 342

<211> 961<211> 961

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 342 <400> 342

<210> 343<210> 343

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 343 <400> 343

<210> 344<210> 344

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 344 <400> 344

<210> 345<210> 345

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 345 <400> 345

<210> 346<210> 346

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 346 <400> 346

<210> 347<210> 347

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 347 <400> 347

<210> 348<210> 348

<211> 861<211> 861

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 348 <400> 348

<210> 349<210> 349

<211> 462<211> 462

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 349 <400> 349

<210> 350<210> 350

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 350 <400> 350

<210> 351<210> 351

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 351 <400> 351

<210> 352<210> 352

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 352 <400> 352

<210> 353<210> 353

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 353 <400> 353

<210> 354<210> 354

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 354 <400> 354

<210> 355<210> 355

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 355 <400> 355

<210> 356<210> 356

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 356 <400> 356

<210> 357<210> 357

<211> 983<211> 983

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 357 <400> 357

<210> 358<210> 358

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 358 <400> 358

<210> 359<210> 359

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 359 <400> 359

<210> 360<210> 360

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 360 <400> 360

<210> 361<210> 361

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 361 <400> 361

<210> 362<210> 362

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 362 <400> 362

<210> 363<210> 363

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 363 <400> 363

<210> 364<210> 364

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 364 <400> 364

<210> 365<210> 365

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 365 <400> 365

<210> 366<210> 366

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 366 <400> 366

<210> 367<210> 367

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 367 <400> 367

<210> 368<210> 368

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 368 <400> 368

<210> 369<210> 369

<211> 987<211> 987

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 369 <400> 369

<210> 370<210> 370

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 370 <400> 370

<210> 371<210> 371

<211> 721<211> 721

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 371 <400> 371

<210> 372<210> 372

<211> 512<211> 512

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 372 <400> 372

<210> 373<210> 373

<211> 965<211> 965

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 373 <400> 373

<210> 374<210> 374

<211> 759<211> 759

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 374 <400> 374

<210> 375<210> 375

<211> 984<211> 984

<212> PRT<212> PRT

<213> 空腸彎曲桿菌<213> Campylobacter jejuni

<400> 375 <400> 375

<210> 376<210> 376

<211> 1003<211> 1003

<212> PRT<212> PRT

<213> 紅嘴鷗彎曲桿菌<213> Campylobacter

<400> 376 <400> 376

<210> 377<210> 377

<211> 372<211> 372

<212> PRT<212> PRT

<213> 候選分類<213> Candidate classification

<400> 377 <400> 377

<210> 378<210> 378

<211> 1117<211> 1117

<212> PRT<212> PRT

<213> 黃褐二氧化碳嗜纖維菌<213> Yellow-Brown Carbon Dioxide

<400> 378 <400> 378

<210> 379<210> 379

<211> 303<211> 303

<212> PRT<212> PRT

<213> 黃褐二氧化碳嗜纖維菌<213> Yellow-Brown Carbon Dioxide

<400> 379 <400> 379

<210> 380<210> 380

<211> 1471<211> 1471

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 二氧化碳嗜纖維菌口腔型324株F0483<223> Carbon dioxide fibrinolytic oral type 324 strain F0483

<400> 380 <400> 380

<210> 381<210> 381

<211> 1450<211> 1450

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 二氧化碳嗜纖維菌口腔型412株F0487<223> Carbon dioxide fibrinolytic oral type 412 strain F0487

<400> 381 <400> 381

<210> 382<210> 382

<211> 1435<211> 1435

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 二氧化碳嗜纖維菌口腔型329株F0087<223> Carbon dioxide fibrinolytic oral 329 strain F0087

<400> 382 <400> 382

<210> 383<210> 383

<211> 1432<211> 1432

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 二氧化碳嗜纖維菌口腔型380株F0488<223> Carbon dioxide fibrinolytic oral 380 strain F0488

<400> 383 <400> 383

<210> 384<210> 384

<211> 1426<211> 1426

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 二氧化碳嗜纖維菌口腔型335株F0486<223> Carbon dioxide fibrinosis oral type 335 strain F0486

<400> 384 <400> 384

<210> 385<210> 385

<211> 1450<211> 1450

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 二氧化碳嗜纖維菌口腔型326株F0382<223> Carbon dioxide fibrinolytic oral 326 strain F0382

<400> 385 <400> 385

<210> 386<210> 386

<211> 1437<211> 1437

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 二氧化碳嗜纖維菌CM59<223> Carbon dioxide fibrin CM59

<400> 386 <400> 386

<210> 387<210> 387

<211> 1140<211> 1140

<212> PRT<212> PRT

<213> 海洋哺乳動物腸球菌<213> Marine mammal enterococci

<400> 387 <400> 387

<210> 388<210> 388

<211> 1419<211> 1419

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 金黃桿菌CF314<223> Golden bacillus CF314

<400> 388 <400> 388

<210> 389<210> 389

<211> 1065<211> 1065

<212> PRT<212> PRT

<213> 產氣夾膜梭菌<213> Clostridium perfringens

<400> 389 <400> 389

<210> 390<210> 390

<211> 1099<211> 1099

<212> PRT<212> PRT

<213> 擁擠棒狀桿菌<213> Crowded Corynebacterium

<400> 390 <400> 390

<210> 391<210> 391

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 白喉桿菌<213> Diphtheria

<400> 391 <400> 391

<210> 392<210> 392

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 白喉桿菌<213> Diphtheria

<400> 392 <400> 392

<210> 393<210> 393

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 白喉桿菌<213> Diphtheria

<400> 393 <400> 393

<210> 394<210> 394

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 白喉桿菌<213> Diphtheria

<400> 394 <400> 394

<210> 395<210> 395

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 白喉桿菌<213> Diphtheria

<400> 395 <400> 395

<210> 396<210> 396

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 白喉桿菌<213> Diphtheria

<400> 396 <400> 396

<210> 397<210> 397

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 白喉桿菌<213> Diphtheria

<400> 397 <400> 397

<210> 398<210> 398

<211> 1069<211> 1069

<212> PRT<212> PRT

<213> 馬氏棒狀桿菌<213> Corynebacterium marxianus

<400> 398 <400> 398

<210> 399<210> 399

<211> 210<211> 210

<212> PRT<212> PRT

<213> 克氏針復球菌<213> Streptococcus mutans

<400> 399 <400> 399

<210> 400<210> 400

<211> 1332<211> 1332

<212> PRT<212> PRT

<213> 豬懶惰狡詐球菌<213> Pig lazy smuggler

<400> 400 <400> 400

<210> 401<210> 401

<211> 921<211> 921

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 401 <400> 401

<210> 402<210> 402

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 402 <400> 402

<210> 403<210> 403

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 403 <400> 403

<210> 404<210> 404

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 404 <400> 404

<210> 405<210> 405

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 405 <400> 405

<210> 406<210> 406

<211> 936<211> 936

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 406 <400> 406

<210> 407<210> 407

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 407 <400> 407

<210> 408<210> 408

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 408 <400> 408

<210> 409<210> 409

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 409 <400> 409

<210> 410<210> 410

<211> 1150<211> 1150

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 410 <400> 410

<210> 411<210> 411

<211> 1150<211> 1150

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 411 <400> 411

<210> 412<210> 412

<211> 1150<211> 1150

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 412 <400> 412

<210> 413<210> 413

<211> 1150<211> 1150

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 413 <400> 413

<210> 414<210> 414

<211> 1150<211> 1150

<212> PRT<212> PRT

<213> 糞腸球菌<213> Enterococcus faecalis

<400> 414 <400> 414

<210> 415<210> 415

<211> 1340<211> 1340

<212> PRT<212> PRT

<213> 屎腸球菌<213> Enterococcus faecium

<400> 415 <400> 415

<210> 416<210> 416

<211> 1339<211> 1339

<212> PRT<212> PRT

<213> 屎腸球菌<213> Enterococcus faecium

<400> 416 <400> 416

<210> 417<210> 417

<211> 1340<211> 1340

<212> PRT<212> PRT

<213> 屎腸球菌<213> Enterococcus faecium

<400> 417 <400> 417

<210> 418<210> 418

<211> 1340<211> 1340

<212> PRT<212> PRT

<213> 屎腸球菌<213> Enterococcus faecium

<400> 418 <400> 418

<210> 419<210> 419

<211> 1339<211> 1339

<212> PRT<212> PRT

<213> 屎腸球菌<213> Enterococcus faecium

<400> 419 <400> 419

<210> 420<210> 420

<211> 1340<211> 1340

<212> PRT<212> PRT

<213> 屎腸球菌<213> Enterococcus faecium

<400> 420 <400> 420

<210> 421<210> 421

<211> 892<211> 892

<212> PRT<212> PRT

<213> 屎腸球菌<213> Enterococcus faecium

<400> 421 <400> 421

<210> 422<210> 422

<211> 1336<211> 1336

<212> PRT<212> PRT

<213> 空腸腸球菌<213> Enterococcus faecalis

<400> 422 <400> 422

<210> 423<210> 423

<211> 116<211> 116

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 腸球菌7L76<223> Enterococcus 7L76

<400> 423 <400> 423

<210> 424<210> 424

<211> 1391<211> 1391

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 真細菌AS15<223> eubacteria AS15

<400> 424 <400> 424

<210> 425<210> 425

<211> 1391<211> 1391

<212> PRT<212> PRT

<213> 尤里真菌<213> Yuri fungus

<400> 425 <400> 425

<210> 426<210> 426

<211> 1142<211> 1142

<212> PRT<212> PRT

<213> 人費克藍姆菌<213> Human Fake gram

<400> 426 <400> 426

<210> 427<210> 427

<211> 1347<211> 1347

<212> PRT<212> PRT

<213> 大分哥德爾菌<213> Oita G.

<400> 427 <400> 427

<210> 428<210> 428

<211> 1348<211> 1348

<212> PRT<212> PRT

<213> 大分哥德爾菌<213> Oita G.

<400> 428 <400> 428

<210> 429<210> 429

<211> 1516<211> 1516

<212> PRT<212> PRT

<213> 黃桿菌<213> Flavobacterium

<400> 429 <400> 429

<210> 430<210> 430

<211> 1629<211> 1629

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 新兒手法朗西斯菌Fx1<223> Newborns Francis Fx1

<400> 430 <400> 430

<210> 431<210> 431

<211> 1646<211> 1646

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 新兒手法朗西斯菌3523<223> New child's hand, R. sinensis 3523

<400> 431 <400> 431

<210> 432<210> 432

<211> 1629<211> 1629

<212> PRT<212> PRT

<213> 新兒手法朗西斯菌<213> Newborns Francis

<400> 432 <400> 432

<210> 433<210> 433

<211> 1629<211> 1629

<212> PRT<212> PRT

<213> 新兒手法朗西斯菌<213> Newborns Francis

<400> 433 <400> 433

<210> 434<210> 434

<211> 244<211> 244

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 434 <400> 434

<210> 435<210> 435

<211> 501<211> 501

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 435 <400> 435

<210> 436<210> 436

<211> 158<211> 158

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 436 <400> 436

<210> 437<210> 437

<211> 878<211> 878

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 437 <400> 437

<210> 438<210> 438

<211> 292<211> 292

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 438 <400> 438

<210> 439<210> 439

<211> 53<211> 53

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 439 <400> 439

<210> 440<210> 440

<211> 393<211> 393

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 440 <400> 440

<210> 441<210> 441

<211> 1629<211> 1629

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 441 <400> 441

<210> 442<210> 442

<211> 285<211> 285

<212> PRT<212> PRT

<213> 土倫病菌<213> Toulon

<400> 442 <400> 442

<210> 443<210> 443

<211> 1323<211> 1323

<212> PRT<212> PRT

<213> 果糖果芽胞桿菌<213> Bacillus licheniformis

<400> 443 <400> 443

<210> 444<210> 444

<211> 1367<211> 1367

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 核棱桿菌3_1_36A2<223> Nuclear bacillus 3_1_36A2

<400> 444 <400> 444

<210> 445<210> 445

<211> 1367<211> 1367

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 核棱桿菌3_1_27<223> Nuclear bacillus 3_1_27

<400> 445 <400> 445

<210> 446<210> 446

<211> 1367<211> 1367

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 核棱桿菌1_1_41FAA<223> Nuclear bacillus 1_1_41FAA

<400> 446 <400> 446

<210> 447<210> 447

<211> 1391<211> 1391

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 黃菌ck-I2-15<223> Yellow bacterium ck-I2-15

<400> 447 <400> 447

<210> 448<210> 448

<211> 1186<211> 1186

<212> PRT<212> PRT

<213> ***加德納菌<213> Gardnerella vaginalis

<400> 448 <400> 448

<210> 449<210> 449

<211> 1186<211> 1186

<212> PRT<212> PRT

<213> ***加德納菌<213> Gardnerella vaginalis

<400> 449 <400> 449

<210> 450<210> 450

<211> 1258<211> 1258

<212> PRT<212> PRT

<213> 溶血李生球菌<213> Hemolytic bacterium

<400> 450 <400> 450

<210> 451<210> 451

<211> 1054<211> 1054

<212> PRT<212> PRT

<213> 副流感嗜血桿菌<213> Haemophilus parainfluenzae

<400> 451 <400> 451

<210> 452<210> 452

<211> 1052<211> 1052

<212> PRT<212> PRT

<213> 副流感嗜血桿菌<213> Haemophilus parainfluenzae

<400> 452 <400> 452

<210> 453<210> 453

<211> 121<211> 121

<212> PRT<212> PRT

<213> 普氏嗜血桿菌<213> Haemophilus

<400> 453 <400> 453

<210> 454<210> 454

<211> 203<211> 203

<212> PRT<212> PRT

<213> 普氏嗜血桿菌<213> Haemophilus

<400> 454 <400> 454

<210> 455<210> 455

<211> 1052<211> 1052

<212> PRT<212> PRT

<213> 生痰嗜血桿菌<213> Haemophilus

<400> 455 <400> 455

<210> 456<210> 456

<211> 1338<211> 1338

<212> PRT<212> PRT

<213> 孔茲創傷球菌<213> Holes Tratococcus

<400> 456 <400> 456

<210> 457<210> 457

<211> 1023<211> 1023

<212> PRT<212> PRT

<213> 淫亂螺桿菌<213> Fornicaria Helicobacter

<400> 457 <400> 457

<210> 458<210> 458

<211> 1023<211> 1023

<212> PRT<212> PRT

<213> 淫亂螺桿菌<213> Fornicaria Helicobacter

<400> 458 <400> 458

<210> 459<210> 459

<211> 344<211> 344

<212> PRT<212> PRT

<213> 胃腸炎螺桿菌<213> Gastroenteritis Helicobacter

<400> 459 <400> 459

<210> 460<210> 460

<211> 1688<211> 1688

<212> PRT<212> PRT

<213> 白因鈉菌<213> White Natto

<400> 460 <400> 460

<210> 461<210> 461

<211> 1354<211> 1354

<212> PRT<212> PRT

<213> 嗜鹼因菌<213> Alkalophilic bacteria

<400> 461 <400> 461

<210> 462<210> 462

<211> 1397<211> 1397

<212> PRT<212> PRT

<213> 海歐特氏菌<213> A. elegans

<400> 462 <400> 462

<210> 463<210> 463

<211> 1060<211> 1060

<212> PRT<212> PRT

<213> 金格桿菌<213> G. gingivalis

<400> 463 <400> 463

<210> 464<210> 464

<211> 1314<211> 1314

<212> PRT<212> PRT

<213> 動物乳酸桿菌<213> Lactobacillus animal

<400> 464 <400> 464

<210> 465<210> 465

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 布氏乳酸桿菌<213> Lactobacillus bulgaricus

<400> 465 <400> 465

<210> 466<210> 466

<211> 315<211> 315

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 466 <400> 466

<210> 467<210> 467

<211> 236<211> 236

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 467 <400> 467

<210> 468<210> 468

<211> 1389<211> 1389

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 468 <400> 468

<210> 469<210> 469

<211> 412<211> 412

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 469 <400> 469

<210> 470<210> 470

<211> 234<211> 234

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 470 <400> 470

<210> 471<210> 471

<211> 566<211> 566

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 471 <400> 471

<210> 472<210> 472

<211> 1363<211> 1363

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 472 <400> 472

<210> 473<210> 473

<211> 1360<211> 1360

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 473 <400> 473

<210> 474<210> 474

<211> 700<211> 700

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 474 <400> 474

<210> 475<210> 475

<211> 330<211> 330

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 475 <400> 475

<210> 476<210> 476

<211> 330<211> 330

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 476 <400> 476

<210> 477<210> 477

<211> 1361<211> 1361

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 477 <400> 477

<210> 478<210> 478

<211> 1128<211> 1128

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 478 <400> 478

<210> 479<210> 479

<211> 1366<211> 1366

<212> PRT<212> PRT

<213> 酪蛋白乳酸桿菌<213> Lactobacillus casein

<400> 479 <400> 479

<210> 480<210> 480

<211> 1354<211> 1354

<212> PRT<212> PRT

<213> 棒狀乳酸桿菌<213> Lactobacillus

<400> 480 <400> 480

<210> 481<210> 481

<211> 544<211> 544

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 481 <400> 481

<210> 482<210> 482

<211> 298<211> 298

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 482 <400> 482

<210> 483<210> 483

<211> 279<211> 279

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 483 <400> 483

<210> 484<210> 484

<211> 538<211> 538

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 484 <400> 484

<210> 485<210> 485

<211> 206<211> 206

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 485 <400> 485

<210> 486<210> 486

<211> 857<211> 857

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 486 <400> 486

<210> 487<210> 487

<211> 857<211> 857

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 487 <400> 487

<210> 488<210> 488

<211> 347<211> 347

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 488 <400> 488

<210> 489<210> 489

<211> 534<211> 534

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 489 <400> 489

<210> 490<210> 490

<211> 278<211> 278

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 490 <400> 490

<210> 491<210> 491

<211> 277<211> 277

<212> PRT<212> PRT

<213> 彎曲乳酸桿菌<213> Lactobacillus

<400> 491 <400> 491

<210> 492<210> 492

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 捲曲乳酸桿菌<213> Lactobacillus

<400> 492 <400> 492

<210> 493<210> 493

<211> 669<211> 669

<212> PRT<212> PRT

<213> 德布律克氏乳酸桿菌<213> Lactobacillus delbrueckii

<400> 493 <400> 493

<210> 494<210> 494

<211> 544<211> 544

<212> PRT<212> PRT

<213> 德布律克氏乳酸桿菌<213> Lactobacillus delbrueckii

<400> 494 <400> 494

<210> 495<210> 495

<211> 1356<211> 1356

<212> PRT<212> PRT

<213> 香腸乳酸桿菌<213> Lactobacillus

<400> 495 <400> 495

<210> 496<210> 496

<211> 1313<211> 1313

<212> PRT<212> PRT

<213> 醱酵乳酸桿菌<213> Lactobacillus fermentum

<400> 496 <400> 496

<210> 497<210> 497

<211> 1327<211> 1327

<212> PRT<212> PRT

<213> 花乳酸桿菌<213> Lactobacillus

<400> 497 <400> 497

<210> 498<210> 498

<211> 1386<211> 1386

<212> PRT<212> PRT

<213> 人乳酸桿菌<213> Lactobacillus human

<400> 498 <400> 498

<210> 499<210> 499

<211> 270<211> 270

<212> PRT<212> PRT

<213> 惰性乳酸桿菌<213> Lactobacillus inertia

<400> 499 <400> 499

<210> 500<210> 500

<211> 255<211> 255

<212> PRT<212> PRT

<213> 惰性乳酸桿菌<213> Lactobacillus inertia

<400> 500 <400> 500

<210> 501<210> 501

<211> 343<211> 343

<212> PRT<212> PRT

<213> 惰性乳酸桿菌<213> Lactobacillus inertia

<400> 501 <400> 501

<210> 502<210> 502

<211> 447<211> 447

<212> PRT<212> PRT

<213> 惰性乳酸桿菌<213> Lactobacillus inertia

<400> 502 <400> 502

<210> 503<210> 503

<211> 667<211> 667

<212> PRT<212> PRT

<213> 惰性乳酸桿菌<213> Lactobacillus inertia

<400> 503 <400> 503

<210> 504<210> 504

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 詹氏乳酸桿菌<213> Lactobacillus japonicus

<400> 504 <400> 504

<210> 505<210> 505

<211> 1382<211> 1382

<212> PRT<212> PRT

<213> 黏膜乳酸桿菌<213> Lactobacillus mucosa

<400> 505 <400> 505

<210> 506<210> 506

<211> 1382<211> 1382

<212> PRT<212> PRT

<213> 戊糖乳酸桿菌<213> Lactobacillus pentosus

<400> 506 <400> 506

<210> 507<210> 507

<211> 1361<211> 1361

<212> PRT<212> PRT

<213> 戊糖乳酸桿菌<213> Lactobacillus pentosus

<400> 507 <400> 507

<210> 508<210> 508

<211> 1358<211> 1358

<212> PRT<212> PRT

<213> 戊糖乳酸桿菌<213> Lactobacillus pentosus

<400> 508 <400> 508

<210> 509<210> 509

<211> 1358<211> 1358

<212> PRT<212> PRT

<213> 胚芽乳酸桿菌<213> Lactobacillus

<400> 509 <400> 509

<210> 510<210> 510

<211> 1361<211> 1361

<212> PRT<212> PRT

<213> 鼠李糖乳酸桿菌<213> Lactobacillus rhamnosus

<400> 510 <400> 510

<210> 511<210> 511

<211> 1361<211> 1361

<212> PRT<212> PRT

<213> 鼠李糖乳酸桿菌<213> Lactobacillus rhamnosus

<400> 511 <400> 511

<210> 512<210> 512

<211> 1352<211> 1352

<212> PRT<212> PRT

<213> 瘤胃乳酸桿菌<213> Lactobacillus rumen

<400> 512 <400> 512

<210> 513<210> 513

<211> 1339<211> 1339

<212> PRT<212> PRT

<213> 唾液乳酸桿菌<213> Lactobacillus saliva

<400> 513 <400> 513

<210> 514<210> 514

<211> 629<211> 629

<212> PRT<212> PRT

<213> 唾液乳酸桿菌<213> Lactobacillus saliva

<400> 514 <400> 514

<210> 515<210> 515

<211> 897<211> 897

<212> PRT<212> PRT

<213> 唾液乳酸桿菌<213> Lactobacillus saliva

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (822)..(822)<222> (822)..(822)

<223> Xaa可為任何天然存在之胺基酸<223> Xaa can be any naturally occurring amino acid

<220><220>

<221> MISC_特徵<221> MISC_Features

<222> (822)..(822)<222> (822)..(822)

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (823)..(823)<222> (823)..(823)

<223> Xaa可為任何天然存在之胺基酸<223> Xaa can be any naturally occurring amino acid

<400> 515 <400> 515

<210> 516<210> 516

<211> 1419<211> 1419

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 乳酸桿菌66c<223> Lactobacillus 66c

<400> 516 <400> 516

<210> 517<210> 517

<211> 1289<211> 1289

<212> PRT<212> PRT

<213> 醃漬乳酸桿菌<213> Lactobacillus marinated

<400> 517 <400> 517

<210> 518<210> 518

<211> 1372<211> 1372

<212> PRT<212> PRT

<213> 退伍軍人嗜肺病菌<213> Veterans of Pneumoconiosis

<400> 518 <400> 518

<210> 519<210> 519

<211> 907<211> 907

<212> PRT<212> PRT

<213> 印度左螺菌<213> Leptospirillum

<400> 519 <400> 519

<210> 520<210> 520

<211> 418<211> 418

<212> PRT<212> PRT

<213> 印度左螺菌<213> Leptospirillum

<400> 520 <400> 520

<210> 521<210> 521

<211> 125<211> 125

<212> PRT<212> PRT

<213> 印度左螺菌<213> Leptospirillum

<400> 521 <400> 521

<210> 522<210> 522

<211> 1355<211> 1355

<212> PRT<212> PRT

<213> 冷明串珠菌<213> Leuconostoc

<400> 522 <400> 522

<210> 523<210> 523

<211> 883<211> 883

<212> PRT<212> PRT

<213> 假腸膜明串珠菌<213> Pseudomonas aeruginosa

<400> 523 <400> 523

<210> 524<210> 524

<211> 468<211> 468

<212> PRT<212> PRT

<213> 假腸膜明串珠菌<213> Pseudomonas aeruginosa

<400> 524 <400> 524

<210> 525<210> 525

<211> 1103<211> 1103

<212> PRT<212> PRT

<213> 無毒李斯特菌<213> Atomic Listeria

<400> 525 <400> 525

<210> 526<210> 526

<211> 1337<211> 1337

<212> PRT<212> PRT

<213> 無毒李斯特菌<213> Atomic Listeria

<400> 526 <400> 526

<210> 527<210> 527

<211> 953<211> 953

<212> PRT<212> PRT

<213> 綿羊李斯特菌<213> Listeria monocytogenes

<400> 527 <400> 527

<210> 528<210> 528

<211> 232<211> 232

<212> PRT<212> PRT

<213> 綿羊李斯特菌<213> Listeria monocytogenes

<400> 528 <400> 528

<210> 529<210> 529

<211> 300<211> 300

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 529 <400> 529

<210> 530<210> 530

<211> 782<211> 782

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<220><220>

<221> MISC_特徵<221> MISC_Features

<222> (722)..(722)<222> (722)..(722)

<223> Xaa可為任何天然存在之胺基酸<223> Xaa can be any naturally occurring amino acid

<400> 530 <400> 530

<210> 531<210> 531

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 531 <400> 531

<210> 532<210> 532

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 532 <400> 532

<210> 533<210> 533

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 533 <400> 533

<210> 534<210> 534

<211> 1099<211> 1099

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 534 <400> 534

<210> 535<210> 535

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 535 <400> 535

<210> 536<210> 536

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 單核球增多性李斯特菌<213> Listeria monocytogenes

<400> 536 <400> 536

<210> 537<210> 537

<211> 874<211> 874

<212> PRT<212> PRT

<213> 西利堅李斯特菌<213> Listeria monocytogenes

<400> 537 <400> 537

<210> 538<210> 538

<211> 1087<211> 1087

<212> PRT<212> PRT

<213> 李斯特菌科細菌<213> Listeria bacteria

<400> 538 <400> 538

<210> 539<210> 539

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 理研菌AK2<223> Phytophthora AK2

<400> 539 <400> 539

<210> 540<210> 540

<211> 1091<211> 1091

<212> PRT<212> PRT

<213> 羞怯動彎桿菌<213> Shame bacillus

<400> 540 <400> 540

<210> 541<210> 541

<211> 1233<211> 1233

<212> PRT<212> PRT

<213> 犬黴漿菌<213> Canine mold

<400> 541 <400> 541

<210> 542<210> 542

<211> 1233<211> 1233

<212> PRT<212> PRT

<213> 犬黴漿菌<213> Canine mold

<400> 542 <400> 542

<210> 543<210> 543

<211> 1233<211> 1233

<212> PRT<212> PRT

<213> 犬黴漿菌<213> Canine mold

<400> 543 <400> 543

<210> 544<210> 544

<211> 1233<211> 1233

<212> PRT<212> PRT

<213> 犬黴漿菌<213> Canine mold

<400> 544 <400> 544

<210> 545<210> 545

<211> 1233<211> 1233

<212> PRT<212> PRT

<213> 犬黴漿菌<213> Canine mold

<400> 545 <400> 545

<210> 546<210> 546

<211> 1239<211> 1239

<212> PRT<212> PRT

<213> 狗黴漿菌<213> Dog Mold

<400> 546 <400> 546

<210> 547<210> 547

<211> 1269<211> 1269

<212> PRT<212> PRT

<213> 雞敗血性黴漿菌<213> Chicken septicum

<400> 547 <400> 547

<210> 548<210> 548

<211> 1224<211> 1224

<212> PRT<212> PRT

<213> 雞敗血性黴漿菌<213> Chicken septicum

<400> 548 <400> 548

<210> 549<210> 549

<211> 1269<211> 1269

<212> PRT<212> PRT

<213> 雞敗血性黴漿菌<213> Chicken septicum

<400> 549 <400> 549

<210> 550<210> 550

<211> 226<211> 226

<212> PRT<212> PRT

<213> 衣阿華黴漿菌<213> Iowa mold

<400> 550 <400> 550

<210> 551<210> 551

<211> 1304<211> 1304

<212> PRT<212> PRT

<213> 滑膜黴漿菌<213> Synovial fungus

<400> 551 <400> 551

<210> 552<210> 552

<211> 1401<211> 1401

<212> PRT<212> PRT

<213> 詹氏類黴菌<213> Jane mold

<400> 552 <400> 552

<210> 553<210> 553

<211> 1466<211> 1466

<212> PRT<212> PRT

<213> 氣味類黴菌<213> Odor mold

<400> 553 <400> 553

<210> 554<210> 554

<211> 241<211> 241

<212> PRT<212> PRT

<213> 淋病奈瑟菌<213> Neisseria gonorrhoeae

<400> 554 <400> 554

<210> 555<210> 555

<211> 666<211> 666

<212> PRT<212> PRT

<213> 淋病奈瑟菌<213> Neisseria gonorrhoeae

<400> 555 <400> 555

<210> 556<210> 556

<211> 828<211> 828

<212> PRT<212> PRT

<213> 淋病奈瑟菌<213> Neisseria gonorrhoeae

<400> 556 <400> 556

<210> 557<210> 557

<211> 408<211> 408

<212> PRT<212> PRT

<213> 淋病奈瑟菌<213> Neisseria gonorrhoeae

<400> 557 <400> 557

<210> 558<210> 558

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 558 <400> 558

<210> 559<210> 559

<211> 976<211> 976

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 559 <400> 559

<210> 560<210> 560

<211> 1081<211> 1081

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 560 <400> 560

<210> 561<210> 561

<211> 1081<211> 1081

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 561 <400> 561

<210> 562<210> 562

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 562 <400> 562

<210> 563<210> 563

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 563 <400> 563

<210> 564<210> 564

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 564 <400> 564

<210> 565<210> 565

<211> 1081<211> 1081

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 565 <400> 565

<210> 566<210> 566

<211> 1081<211> 1081

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 566 <400> 566

<210> 567<210> 567

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 567 <400> 567

<210> 568<210> 568

<211> 1081<211> 1081

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 568 <400> 568

<210> 569<210> 569

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 569 <400> 569

<210> 570<210> 570

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 570 <400> 570

<210> 571<210> 571

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 571 <400> 571

<210> 572<210> 572

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 572 <400> 572

<210> 573<210> 573

<211> 1082<211> 1082

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 573 <400> 573

<210> 574<210> 574

<211> 67<211> 67

<212> PRT<212> PRT

<213> 腦膜炎雙球菌<213> Meningococcus

<400> 574 <400> 574

<210> 575<210> 575

<211> 220<211> 220

<212> PRT<212> PRT

<213> 黏膜奈瑟菌<213> Neisseria mutagen

<400> 575 <400> 575

<210> 576<210> 576

<211> 392<211> 392

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 奈瑟菌口腔型20株F0370<223> Neisseria oral type 20 strain F0370

<400> 576 <400> 576

<210> 577<210> 577

<211> 701<211> 701

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 奈瑟菌口腔型20株F0370<223> Neisseria oral type 20 strain F0370

<400> 577 <400> 577

<210> 578<210> 578

<211> 1089<211> 1089

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 奈瑟菌口腔型14株F0314<223> Neisseria oral type 14 strain F0314

<400> 578 <400> 578

<210> 579<210> 579

<211> 1097<211> 1097

<212> PRT<212> PRT

<213> 沃斯沃奈瑟菌<213> Voswo Neiss

<400> 579 <400> 579

<210> 580<210> 580

<211> 1426<211> 1426

<212> PRT<212> PRT

<213> 土壤尼阿菌<213> Soil Nea

<400> 580 <400> 580

<210> 581<210> 581

<211> 79<211> 79

<212> PRT<212> PRT

<213> 鹽鹼湖桿菌<213> Hulo-L.

<400> 581 <400> 581

<210> 582<210> 582

<211> 1498<211> 1498

<212> PRT<212> PRT

<213> 藍氏氣味菌<213> Blue's odor bacteria

<400> 582 <400> 582

<210> 583<210> 583

<211> 1389<211> 1389

<212> PRT<212> PRT

<213> 變形酒球菌<213> Deformed bacterium

<400> 583 <400> 583

<210> 584<210> 584

<211> 1535<211> 1535

<212> PRT<212> PRT

<213> 火雞鼻氣管鳥桿菌<213> turkey nasal tracheal bacillus

<400> 584 <400> 584

<210> 585<210> 585

<211> 103<211> 103

<212> PRT<212> PRT

<213> 奠副類桿菌<213>

<400> 585 <400> 585

<210> 586<210> 586

<211> 82<211> 82

<212> PRT<212> PRT

<213> 奠副類桿菌<213>

<400> 586 <400> 586

<210> 587<210> 587

<211> 84<211> 84

<212> PRT<212> PRT

<213> 奠副類桿菌<213>

<400> 587 <400> 587

<210> 588<210> 588

<211> 398<211> 398

<212> PRT<212> PRT

<213> 貝氏巴斯德菌<213> Pasteurella bass

<400> 588 <400> 588

<210> 589<210> 589

<211> 610<211> 610

<212> PRT<212> PRT

<213> 貝氏巴斯德菌<213> Pasteurella bass

<400> 589 <400> 589

<210> 590<210> 590

<211> 199<211> 199

<212> PRT<212> PRT

<213> 敗血性巴氏桿菌<213> Pasteurella septicum

<400> 590 <400> 590

<210> 591<210> 591

<211> 63<211> 63

<212> PRT<212> PRT

<213> 敗血性巴氏桿菌<213> Pasteurella septicum

<400> 591 <400> 591

<210> 592<210> 592

<211> 1058<211> 1058

<212> PRT<212> PRT

<213> 敗血性巴氏桿菌<213> Pasteurella septicum

<400> 592 <400> 592

<210> 593<210> 593

<211> 1056<211> 1056

<212> PRT<212> PRT

<213> 敗血性巴氏桿菌<213> Pasteurella septicum

<400> 593 <400> 593

<210> 594<210> 594

<211> 134<211> 134

<212> PRT<212> PRT

<213> 敗血性巴氏桿菌<213> Pasteurella septicum

<400> 594 <400> 594

<210> 595<210> 595

<211> 53<211> 53

<212> PRT<212> PRT

<213> 敗血性巴氏桿菌<213> Pasteurella septicum

<400> 595 <400> 595

<210> 596<210> 596

<211> 1366<211> 1366

<212> PRT<212> PRT

<213> 乳酸片球菌<213> Pediococcus lactis

<400> 596 <400> 596

<210> 597<210> 597

<211> 1229<211> 1229

<212> PRT<212> PRT

<213> 乳酸片球菌<213> Pediococcus lactis

<400> 597 <400> 597

<210> 598<210> 598

<211> 270<211> 270

<212> PRT<212> PRT

<213> 羅氏片球菌<213> Pediococcus rosenbergii

<400> 598 <400> 598

<210> 599<210> 599

<211> 1016<211> 1016

<212> PRT<212> PRT

<213> 羅氏片球菌<213> Pediococcus rosenbergii

<400> 599 <400> 599

<210> 600<210> 600

<211> 1333<211> 1333

<212> PRT<212> PRT

<213> 南極微球菌<213> Antarctic Micrococci

<400> 600 <400> 600

<210> 601<210> 601

<211> 211<211> 211

<212> PRT<212> PRT

<213> 犬口腔？？單胞菌<213> Canine mouth? ? Monocytogenes

<400> 601 <400> 601

<210> 602<210> 602

<211> 1009<211> 1009

<212> PRT<212> PRT

<213> 犬口腔？？單胞菌<213> Canine mouth? ? Monocytogenes

<400> 602 <400> 602

<210> 603<210> 603

<211> 1197<211> 1197

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> ？？單胞菌口腔型279株F0450<223> ? ? Monocytogenes oral type 279 strain F0450

<400> 603 <400> 603

<210> 604<210> 604

<211> 1422<211> 1422

<212> PRT<212> PRT

<213> 西牙普雷沃氏菌<213> Prevotella falciparum

<400> 604 <400> 604

<210> 605<210> 605

<211> 443<211> 443

<212> PRT<212> PRT

<213> 解糖普雷沃氏菌<213> Prednisone

<400> 605 <400> 605

<210> 606<210> 606

<211> 1375<211> 1375

<212> PRT<212> PRT

<213> 組織普雷沃氏菌<213> Tissue Prevo

<400> 606 <400> 606

<210> 607<210> 607

<211> 1380<211> 1380

<212> PRT<212> PRT

<213> 中間普雷沃氏菌<213> Prevotella intermedia

<400> 607 <400> 607

<210> 608<210> 608

<211> 129<211> 129

<212> PRT<212> PRT

<213> 多形普雷沃氏菌<213> Prevotella polymorpha

<400> 608 <400> 608

<210> 609<210> 609

<211> 535<211> 535

<212> PRT<212> PRT

<213> 多形普雷沃氏菌<213> Prevotella polymorpha

<400> 609 <400> 609

<210> 610<210> 610

<211> 1380<211> 1380

<212> PRT<212> PRT

<213> 變黑普雷沃氏菌<213> P. burgdorferi

<400> 610 <400> 610

<210> 611<210> 611

<211> 1506<211> 1506

<212> PRT<212> PRT

<213> 變黑普雷沃氏菌<213> P. burgdorferi

<400> 611 <400> 611

<210> 612<210> 612

<211> 774<211> 774

<212> PRT<212> PRT

<213> 齦炎普雷沃氏菌<213> Prevotella vivax

<400> 612 <400> 612

<210> 613<210> 613

<211> 691<211> 691

<212> PRT<212> PRT

<213> 齦炎普雷沃氏菌<213> Prevotella vivax

<400> 613 <400> 613

<210> 614<210> 614

<211> 242<211> 242

<212> PRT<212> PRT

<213> 解糖普雷沃氏菌<213> Prednisone

<400> 614 <400> 614

<210> 615<210> 615

<211> 1174<211> 1174

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 普雷沃氏菌口腔型317株F0108<223> Prevo's oral 317 strain F0108

<400> 615 <400> 615

<210> 616<210> 616

<211> 992<211> 992

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 普雷沃氏菌口腔型472株F0295<223> Prevo's oral type 472 strain F0295

<400> 616 <400> 616

<210> 617<210> 617

<211> 1375<211> 1375

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 普雷沃氏菌口腔型306株F0472<223> Prevo's oral type 306 strain F0472

<400> 617 <400> 617

<210> 618<210> 618

<211> 1483<211> 1483

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 普雷沃氏菌MSX73<223> Prevobacterium MSX73

<400> 618 <400> 618

<210> 619<210> 619

<211> 593<211> 593

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 普雷沃氏菌口腔型317株F0108<223> Prevo's oral 317 strain F0108

<400> 619 <400> 619

<210> 620<210> 620

<211> 1424<211> 1424

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 普雷沃氏菌C561<223> Prevo C561

<400> 620 <400> 620

<210> 621<210> 621

<211> 241<211> 241

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 普雷沃氏菌口腔型472株F0295<223> Prevo's oral type 472 strain F0295

<400> 621 <400> 621

<210> 622<210> 622

<211> 1216<211> 1216

<212> PRT<212> PRT

<213> 糞普雷沃氏菌<213> Prevotella faecalis

<400> 622 <400> 622

<210> 623<210> 623

<211> 1487<211> 1487

<212> PRT<212> PRT

<213> 替莫普雷沃氏菌<213> T. viva

<400> 623 <400> 623

<210> 624<210> 624

<211> 770<211> 770

<212> PRT<212> PRT

<213> 解乳酸假胺菌<213> Solution to pseudo-ammonium lactate

<400> 624 <400> 624

<210> 625<210> 625

<211> 103<211> 103

<212> PRT<212> PRT

<213> 菜豆根瘤菌<213> Rhizobium Bean

<400> 625 <400> 625

<210> 626<210> 626

<211> 1059<211> 1059

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 紅細菌PH10<223> Red bacteria PH10

<400> 626 <400> 626

<210> 627<210> 627

<211> 1405<211> 1405

<212> PRT<212> PRT

<213> 鴨疫黎氏桿菌<213> R. faecalis

<400> 627 <400> 627

<210> 628<210> 628

<211> 1145<211> 1145

<212> PRT<212> PRT

<213> 鴨疫黎氏桿菌<213> R. faecalis

<400> 628 <400> 628

<210> 629<210> 629

<211> 1400<211> 1400

<212> PRT<212> PRT

<213> 鴨疫黎氏桿菌<213> R. faecalis

<400> 629 <400> 629

<210> 630<210> 630

<211> 1128<211> 1128

<212> PRT<212> PRT

<213> 腸羅斯菌<213> Rhizobacteria

<400> 630 <400> 630

<210> 631<210> 631

<211> 1471<211> 1471

<212> PRT<212> PRT

<213> 魏氏史卡都菌<213> S. cerevisiae

<400> 631 <400> 631

<210> 632<210> 632

<211> 116<211> 116

<212> PRT<212> PRT

<213> 食神鞘氨醇桿菌<213> Sphingomonas

<400> 632 <400> 632

<210> 633<210> 633

<211> 1306<211> 1306

<212> PRT<212> PRT

<213> 食神鞘氨醇桿菌<213> Sphingomonas

<400> 633 <400> 633

<210> 634<210> 634

<211> 1110<211> 1110

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鞘脂菌AP49<223> Sphingolipid AP49

<400> 634 <400> 634

<210> 635<210> 635

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 對益生菌乳酸桿菌<213> Probiotics Lactobacillus

<400> 635 <400> 635

<210> 636<210> 636

<211> 475<211> 475

<212> PRT<212> PRT

<213> 馬斯里葡萄球菌<213> Masri Staphylococcus

<400> 636 <400> 636

<210> 637<210> 637

<211> 581<211> 581

<212> PRT<212> PRT

<213> 馬斯里葡萄球菌<213> Masri Staphylococcus

<400> 637 <400> 637

<210> 638<210> 638

<211> 1334<211> 1334

<212> PRT<212> PRT

<213> 金黃色葡萄球菌<213> Staphylococcus aureus

<400> 638 <400> 638

<210> 639<210> 639

<211> 1112<211> 1112

<212> PRT<212> PRT

<213> 模仿葡萄球菌<213> Mimics Staphylococcus

<400> 639 <400> 639

<210> 640<210> 640

<211> 773<211> 773

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 640 <400> 640

<210> 641<210> 641

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 641 <400> 641

<210> 642<210> 642

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 642 <400> 642

<210> 643<210> 643

<211> 1378<211> 1378

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 643 <400> 643

<210> 644<210> 644

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 644 <400> 644

<210> 645<210> 645

<211> 1377<211> 1377

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 645 <400> 645

<210> 646<210> 646

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<220><220>

<221> MISC_特徵<221> MISC_Features

<222> (117)..(117)<222> (117)..(117)

<223> Xaa可為任何天然存在之胺基酸<223> Xaa can be any naturally occurring amino acid

<400> 646 <400> 646

<210> 647<210> 647

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 647 <400> 647

<210> 648<210> 648

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<400> 648 <400> 648

<210> 649<210> 649

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 無乳鏈球菌<213> Streptococcus agalactiae

<220><220>

<221> MISC_特徵<221> MISC_Features

<222> (9)..(9)<222> (9)..(9)

<223> Xaa可為任何天然存在之胺基酸<223> Xaa can be any naturally occurring amino acid

<400> 649 <400> 649

<210> 650<210> 650

<211> 1125<211> 1125

<212> PRT<212> PRT

<213> 咽峽炎鏈球菌<213> Streptococcus angina

<400> 650 <400> 650

<210> 651<210> 651

<211> 1386<211> 1386

<212> PRT<212> PRT

<213> 咽峽炎鏈球菌<213> Streptococcus angina

<400> 651 <400> 651

<210> 652<210> 652

<211> 1396<211> 1396

<212> PRT<212> PRT

<213> 咽峽炎鏈球菌<213> Streptococcus angina

<400> 652 <400> 652

<210> 653<210> 653

<211> 1375<211> 1375

<212> PRT<212> PRT

<213> 犬鏈球菌<213> Streptococcus canis

<400> 653 <400> 653

<210> 654<210> 654

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 星群鏈球菌<213> Streptococcus mutans

<400> 654 <400> 654

<210> 655<210> 655

<211> 538<211> 538

<212> PRT<212> PRT

<213> 壞乳鏈球菌<213> Streptococcus faecalis

<400> 655 <400> 655

<210> 656<210> 656

<211> 1155<211> 1155

<212> PRT<212> PRT

<213> 壞乳鏈球菌<213> Streptococcus faecalis

<400> 656 <400> 656

<210> 657<210> 657

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 壞乳鏈球菌<213> Streptococcus faecalis

<400> 657 <400> 657

<210> 658<210> 658

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 壞乳鏈球菌<213> Streptococcus faecalis

<400> 658 <400> 658

<210> 659<210> 659

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 壞乳鏈球菌<213> Streptococcus faecalis

<400> 659 <400> 659

<210> 660<210> 660

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 解沒食子酸鏈球菌<213> Streptomyces gallis

<400> 660 <400> 660

<210> 661<210> 661

<211> 1375<211> 1375

<212> PRT<212> PRT

<213> 嬰兒鏈球菌<213> Streptococcus streptococci

<400> 661 <400> 661

<210> 662<210> 662

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 海豚鏈球菌<213> Streptococcus mutans

<400> 662 <400> 662

<210> 663<210> 663

<211> 1392<211> 1392

<212> PRT<212> PRT

<213> 和緩鏈球菌<213> Streptococcus mutans

<400> 663 <400> 663

<210> 664<210> 664

<211> 1134<211> 1134

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 664 <400> 664

<210> 665<210> 665

<211> 1134<211> 1134

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 665 <400> 665

<210> 666<210> 666

<211> 1128<211> 1128

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 666 <400> 666

<210> 667<210> 667

<211> 1128<211> 1128

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 667 <400> 667

<210> 668<210> 668

<211> 1338<211> 1338

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 668 <400> 668

<210> 669<210> 669

<211> 1338<211> 1338

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 669 <400> 669

<210> 670<210> 670

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 670 <400> 670

<210> 671<210> 671

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 671 <400> 671

<210> 672<210> 672

<211> 1229<211> 1229

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 672 <400> 672

<210> 673<210> 673

<211> 1229<211> 1229

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 673 <400> 673

<210> 674<210> 674

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 674 <400> 674

<210> 675<210> 675

<211> 1350<211> 1350

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 675 <400> 675

<210> 676<210> 676

<211> 1350<211> 1350

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 676 <400> 676

<210> 677<210> 677

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 677 <400> 677

<210> 678<210> 678

<211> 1350<211> 1350

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 678 <400> 678

<210> 679<210> 679

<211> 1350<211> 1350

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 679 <400> 679

<210> 680<210> 680

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 680 <400> 680

<210> 681<210> 681

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 681 <400> 681

<210> 682<210> 682

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 682 <400> 682

<210> 683<210> 683

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 683 <400> 683

<210> 684<210> 684

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 684 <400> 684

<210> 685<210> 685

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 685 <400> 685

<210> 686<210> 686

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 686 <400> 686

<210> 687<210> 687

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 687 <400> 687

<210> 688<210> 688

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 688 <400> 688

<210> 689<210> 689

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 689 <400> 689

<210> 690<210> 690

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 690 <400> 690

<210> 691<210> 691

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 691 <400> 691

<210> 692<210> 692

<211> 1359<211> 1359

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 692 <400> 692

<210> 693<210> 693

<211> 1359<211> 1359

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 693 <400> 693

<210> 694<210> 694

<211> 1355<211> 1355

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 694 <400> 694

<210> 695<210> 695

<211> 1355<211> 1355

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 695 <400> 695

<210> 696<210> 696

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 696 <400> 696

<210> 697<210> 697

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 697 <400> 697

<210> 698<210> 698

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 698 <400> 698

<210> 699<210> 699

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 699 <400> 699

<210> 700<210> 700

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 700 <400> 700

<210> 701<210> 701

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 701 <400> 701

<210> 702<210> 702

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 702 <400> 702

<210> 703<210> 703

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 703 <400> 703

<210> 704<210> 704

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 704 <400> 704

<210> 705<210> 705

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 705 <400> 705

<210> 706<210> 706

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 706 <400> 706

<210> 707<210> 707

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 707 <400> 707

<210> 708<210> 708

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 708 <400> 708

<210> 709<210> 709

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 709 <400> 709

<210> 710<210> 710

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 710 <400> 710

<210> 711<210> 711

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 711 <400> 711

<210> 712<210> 712

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 712 <400> 712

<210> 713<210> 713

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 713 <400> 713

<210> 714<210> 714

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 714 <400> 714

<210> 715<210> 715

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 715 <400> 715

<210> 716<210> 716

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 716 <400> 716

<210> 717<210> 717

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 717 <400> 717

<210> 718<210> 718

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 718 <400> 718

<210> 719<210> 719

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 719 <400> 719

<210> 720<210> 720

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 720 <400> 720

<210> 721<210> 721

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 721 <400> 721

<210> 722<210> 722

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 722 <400> 722

<210> 723<210> 723

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 723 <400> 723

<210> 724<210> 724

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 724 <400> 724

<210> 725<210> 725

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 725 <400> 725

<210> 726<210> 726

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 726 <400> 726

<210> 727<210> 727

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 727 <400> 727

<210> 728<210> 728

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 728 <400> 728

<210> 729<210> 729

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 729 <400> 729

<210> 730<210> 730

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 730 <400> 730

<210> 731<210> 731

<211> 1350<211> 1350

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 731 <400> 731

<210> 732<210> 732

<211> 1350<211> 1350

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 732 <400> 732

<210> 733<210> 733

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 733 <400> 733

<210> 734<210> 734

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 734 <400> 734

<210> 735<210> 735

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 735 <400> 735

<210> 736<210> 736

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 736 <400> 736

<210> 737<210> 737

<211> 1345<211> 1345

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 737 <400> 737

<210> 738<210> 738

<211> 1355<211> 1355

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 738 <400> 738

<210> 739<210> 739

<211> 1355<211> 1355

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 739 <400> 739

<210> 740<210> 740

<211> 1125<211> 1125

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 740 <400> 740

<210> 741<210> 741

<211> 1125<211> 1125

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 741 <400> 741

<210> 742<210> 742

<211> 1125<211> 1125

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 742 <400> 742

<210> 743<210> 743

<211> 1125<211> 1125

<212> PRT<212> PRT

<213> 變種鏈球菌<213> Streptococcus mutans

<400> 743 <400> 743

<210> 744<210> 744

<211> 670<211> 670

<212> PRT<212> PRT

<213> 口腔鏈球菌<213> Streptococcus oralis

<400> 744 <400> 744

<210> 745<210> 745

<211> 1373<211> 1373

<212> PRT<212> PRT

<213> 口腔鏈球菌<213> Streptococcus oralis

<400> 745 <400> 745

<210> 746<210> 746

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 口腔鏈球菌<213> Streptococcus oralis

<400> 746 <400> 746

<210> 747<210> 747

<211> 1121<211> 1121

<212> PRT<212> PRT

<213> 口腔鏈球菌<213> Streptococcus oralis

<400> 747 <400> 747

<210> 748<210> 748

<211> 1134<211> 1134

<212> PRT<212> PRT

<213> 口腔鏈球菌<213> Streptococcus oralis

<400> 748 <400> 748

<210> 749<210> 749

<211> 550<211> 550

<212> PRT<212> PRT

<213> 口腔鏈球菌<213> Streptococcus oralis

<400> 749 <400> 749

<210> 750<210> 750

<211> 1140<211> 1140

<212> PRT<212> PRT

<213> 副血鏈球菌<213> Streptococcus mutans

<400> 750 <400> 750

<210> 751<210> 751

<211> 1374<211> 1374

<212> PRT<212> PRT

<213> 假刺鏈球菌<213> S. sphaericus

<400> 751 <400> 751

<210> 752<210> 752

<211> 1052<211> 1052

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 752 <400> 752

<210> 753<210> 753

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 753 <400> 753

<210> 754<210> 754

<211> 1367<211> 1367

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 754 <400> 754

<210> 755<210> 755

<211> 1368<211> 1368

<212> PRT<212> PRT

<213> 釀膿鏈球菌<213> Streptococcus pyogenes

<400> 755 <400> 755

<210> 756<210> 756

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 鼠鏈球菌<213> Streptococcus suis

<400> 756 <400> 756

<210> 757<210> 757

<211> 1135<211> 1135

<212> PRT<212> PRT

<213> 涎鏈球菌<213> Streptococcus mutans

<400> 757 <400> 757

<210> 758<210> 758

<211> 1127<211> 1127

<212> PRT<212> PRT

<213> 涎鏈球菌<213> Streptococcus mutans

<400> 758 <400> 758

<210> 759<210> 759

<211> 1385<211> 1385

<212> PRT<212> PRT

<213> 涎鏈球菌<213> Streptococcus mutans

<400> 759 <400> 759

<210> 760<210> 760

<211> 1392<211> 1392

<212> PRT<212> PRT

<213> 犬鏈球菌<213> Streptococcus canis

<400> 760 <400> 760

<210> 761<210> 761

<211> 1377<211> 1377

<212> PRT<212> PRT

<213> 犬鏈球菌<213> Streptococcus canis

<400> 761 <400> 761

<210> 762<210> 762

<211> 1370<211> 1370

<212> PRT<212> PRT

<213> 犬鏈球菌<213> Streptococcus canis

<400> 762 <400> 762

<210> 763<210> 763

<211> 1421<211> 1421

<212> PRT<212> PRT

<213> 犬鏈球菌<213> Streptococcus canis

<400> 763 <400> 763

<210> 764<210> 764

<211> 317<211> 317

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌GMD4S<223> Streptococcus GMD4S

<400> 764 <400> 764

<210> 765<210> 765

<211> 1420<211> 1420

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌口腔型071株73H25AP<223> Streptococcus oral type 071 strain 73H25AP

<400> 765 <400> 765

<210> 766<210> 766

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌F0441<223> Streptococcus F0441

<400> 766 <400> 766

<210> 767<210> 767

<211> 93<211> 93

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌BS35b<223> Streptococcus BS35b

<400> 767 <400> 767

<210> 768<210> 768

<211> 1121<211> 1121

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌GMD6S<223> Streptococcus GMD6S

<400> 768 <400> 768

<210> 769<210> 769

<211> 1026<211> 1026

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌BS35b<223> Streptococcus BS35b

<400> 769 <400> 769

<210> 770<210> 770

<211> 1377<211> 1377

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌C300<223> Streptococcus C300

<400> 770 <400> 770

<210> 771<210> 771

<211> 1371<211> 1371

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌口腔型056株F0418<223> Streptococcus oral type 056 strain F0418

<400> 771 <400> 771

<210> 772<210> 772

<211> 1139<211> 1139

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌C150<223> Streptococcus C150

<400> 772 <400> 772

<210> 773<210> 773

<211> 1375<211> 1375

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌M334<223> Streptococcus M334

<400> 773 <400> 773

<210> 774<210> 774

<211> 206<211> 206

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 鏈球菌GMD4S<223> Streptococcus GMD4S

<400> 774 <400> 774

<210> 775<210> 775

<211> 1122<211> 1122

<212> PRT<212> PRT

<213> 豬鏈球菌<213> Streptococcus suis

<400> 775 <400> 775

<210> 776<210> 776

<211> 1381<211> 1381

<212> PRT<212> PRT

<213> 豬鏈球菌<213> Streptococcus suis

<400> 776 <400> 776

<210> 777<210> 777

<211> 39<211> 39

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 777 <400> 777

<210> 778<210> 778

<211> 302<211> 302

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 778 <400> 778

<210> 779<210> 779

<211> 1121<211> 1121

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 779 <400> 779

<210> 780<210> 780

<211> 1121<211> 1121

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 780 <400> 780

<210> 781<210> 781

<211> 1121<211> 1121

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 781 <400> 781

<210> 782<210> 782

<211> 1122<211> 1122

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 782 <400> 782

<210> 783<210> 783

<211> 1388<211> 1388

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 783 <400> 783

<210> 784<210> 784

<211> 1388<211> 1388

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 784 <400> 784

<210> 785<210> 785

<211> 595<211> 595

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 785 <400> 785

<210> 786<210> 786

<211> 1388<211> 1388

<212> PRT<212> PRT

<213> 嗜熱鏈球菌<213> Streptococcus thermophilus

<400> 786 <400> 786

<210> 787<210> 787

<211> 1038<211> 1038

<212> PRT<212> PRT

<213> 前庭鏈球菌<213> vestibular streptococci

<400> 787 <400> 787

<210> 788<210> 788

<211> 97<211> 97

<212> PRT<212> PRT

<213> 前庭鏈球菌<213> vestibular streptococci

<400> 788 <400> 788

<210> 789<210> 789

<211> 1084<211> 1084

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 罕見小球菌4_3_54A2FAA<223> Rare bacterium 4_3_54A2FAA

<400> 789 <400> 789

<210> 790<210> 790

<211> 951<211> 951

<212> PRT<212> PRT

<213> 小兒華德薩特菌<213> Pediatric Waldenella

<400> 790 <400> 790

<210> 791<210> 791

<211> 406<211> 406

<212> PRT<212> PRT

<213> 小兒華德薩特菌<213> Pediatric Waldenella

<400> 791 <400> 791

<210> 792<210> 792

<211> 389<211> 389

<212> PRT<212> PRT

<213> 華德薩特菌<213> Waldstatella

<400> 792 <400> 792

<210> 793<210> 793

<211> 976<211> 976

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 福賽坦氏菌6_1_58FAA_CT1<223> Forsythia 6_1_58FAA_CT1

<400> 793 <400> 793

<210> 794<210> 794

<211> 1049<211> 1049

<212> PRT<212> PRT

<213> 運動替斯崔納菌<213> Sport Steinerella

<400> 794 <400> 794

<210> 795<210> 795

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 795 <400> 795

<210> 796<210> 796

<211> 769<211> 769

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 796 <400> 796

<210> 797<210> 797

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 797 <400> 797

<210> 798<210> 798

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 798 <400> 798

<210> 799<210> 799

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 799 <400> 799

<210> 800<210> 800

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 800 <400> 800

<210> 801<210> 801

<211> 357<211> 357

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 801 <400> 801

<210> 802<210> 802

<211> 1395<211> 1395

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 802 <400> 802

<210> 803<210> 803

<211> 631<211> 631

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 803 <400> 803

<210> 804<210> 804

<211> 631<211> 631

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 804 <400> 804

<210> 805<210> 805

<211> 370<211> 370

<212> PRT<212> PRT

<213> 齒垢密螺旋體<213> tartar

<400> 805 <400> 805

<210> 806<210> 806

<211> 591<211> 591

<212> PRT<212> PRT

<213> 食果膠密螺旋體<213> Pectin

<400> 806 <400> 806

<210> 807<210> 807

<211> 1062<211> 1062

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 密螺旋體JC4<223> Treponema pallidum JC4

<400> 807 <400> 807

<210> 808<210> 808

<211> 281<211> 281

<212> PRT<212> PRT

<213> 文氏密螺旋體<213> Helicobacter burgdorferi

<400> 808 <400> 808

<210> 809<210> 809

<211> 675<211> 675

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 未經培養之細菌T3_7_42578<223> Uncultivated bacteria T3_7_42578

<400> 809 <400> 809

<210> 810<210> 810

<211> 1017<211> 1017

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 未經培養之細菌<223> Uncultivated bacteria

<400> 810 <400> 810

<210> 811<210> 811

<211> 600<211> 600

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 未經培養之細菌<223> Uncultivated bacteria

<400> 811 <400> 811

<210> 812<210> 812

<211> 1011<211> 1011

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 未經取代之δ 變形菌HF0070_07E19<223> Unsubstituted δ- proteobacteria HF0070_07E19

<400> 812 <400> 812

<210> 813<210> 813

<211> 1011<211> 1011

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 未經取代之δ 變形菌HF0070_07E19<223> Unsubstituted δ- proteobacteria HF0070_07E19

<400> 813 <400> 813

<210> 814<210> 814

<211> 1120<211> 1120

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> 韋永氏球菌口腔型780株F0422<223> Wyvernia oral 780 strain F0422

<400> 814 <400> 814

<210> 815<210> 815

<211> 983<211> 983

<212> PRT<212> PRT

<213> 新校變磷桿菌<213> New school

<400> 815 <400> 815

<210> 816<210> 816

<211> 94<211> 94

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 816 <400> 816

<210> 817<210> 817

<211> 22<211> 22

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 817 <400> 817

<210> 818<210> 818

<211> 36<211> 36

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 818 <400> 818

<210> 819<210> 819

<211> 10<211> 10

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 819 <400> 819

<210> 820<210> 820

<211> 15<211> 15

<212> DNA<212> DNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 820 <400> 820

<210> 821<210> 821

<211> 73<211> 73

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 821 <400> 821

<210> 822<210> 822

<211> 20<211> 20

<212> DNA<212> DNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 822 <400> 822

<210> 823<210> 823

<211> 20<211> 20

<212> DNA<212> DNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 823 <400> 823

<210> 824<210> 824

<211> 125<211> 125

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (13)..(112)<222> (13)..(112)

<223> 在每個位置之n可存在或不存在，使得此區域可含有3至100個核？酸。n為a、c、g或u。<223> The n at each position may or may not exist so that this area can contain 3 to 100 cores? acid. n is a, c, g or u.

<400> 824 <400> 824

<210> 825<210> 825

<211> 123<211> 123

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (12)..(111)<222> (12)..(111)

<223> 在每個位置之n可存在或不存在，使得此區域可含有3至100個核？酸。n為a、c、g或u。<223> The n at each position may or may not exist so that this area can contain 3 to 100 cores? acid. n is a, c, g or u.

<400> 825 <400> 825

<210> 826<210> 826

<211> 124<211> 124

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (13)..(112)<222> (13)..(112)

<223> 在每個位置之n可存在或不存在，使得此區域可含有3至100個核？酸。n為a、c、g或u。<223> The n at each position may or may not exist so that this area can contain 3 to 100 cores? acid. n is a, c, g or u.

<400> 826 <400> 826

<210> 827<210> 827

<211> 128<211> 128

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (14)..(113)<222> (14)..(113)

<223> 在每個位置之n可存在或不存在，使得此區域可含有3至100個核？酸。n為a、c、g或u。<223> The n at each position may or may not exist so that this area can contain 3 to 100 cores? acid. n is a, c, g or u.

<400> 827 <400> 827

<210> 828<210> 828

<211> 122<211> 122

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (12)..(111)<222> (12)..(111)

<223> 在每個位置之n可存在或不存在，使得此區域可含有3至100個核？酸。n為a、c、g或u。<223> The n at each position may or may not exist so that this area can contain 3 to 100 cores? acid. n is a, c, g or u.

<400> 828 <400> 828

<210> 829<210> 829

<211> 42<211> 42

<212> RNA<212> RNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> 合成之核酸序列<223> Synthetic nucleic acid sequence

<400> 829 <400> 829

<210> 830<210> 830

<211> 7<211> 7

<212> PRT<212> PRT

<213> 猴病毒40<213> Monkey virus 40

<400> 830 <400> 830

<210> 831<210> 831

<211> 16<211> 16

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> /note="未知敘述：核胞漿素二體NLS序列"<223> /note="Unknown narrative: nuclear cytosolic two-body NLS sequence"

<400> 831 <400> 831

<210> 832<210> 832

<211> 9<211> 9

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> /note="未知敘述：C-myc NLS序列"<223> /note="Unknown Description: C-myc NLS Sequence"

<400> 832 <400> 832

<210> 833<210> 833

<211> 11<211> 11

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> /note="未知敘述：C-myc NLS序列"<223> /note="Unknown Description: C-myc NLS Sequence"

<400> 833 <400> 833

<210> 834<210> 834

<211> 38<211> 38

<212> PRT<212> PRT

<213> 人<213> People

<400> 834 <400> 834

<210> 835<210> 835

<211> 42<211> 42

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> /note="未知敘述：內輸蛋白α 序列IBB結構域"<223>/note="Unknown narrative: endogenous protein alpha sequence IBB domain"

<220><220>

<221> misc_特徵<221> misc_ feature

<222> (5)..(5)<222> (5)..(5)

<223> Xaa可為任何天然存在之胺基酸<223> Xaa can be any naturally occurring amino acid

<400> 835 <400> 835

<210> 836<210> 836

<211> 8<211> 8

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> /note="D未知敘述：Myoma T蛋白序列"<223> /note="DUnknown Narrative: Myoma T Protein Sequence"

<400> 836 <400> 836

<210> 837<210> 837

<211> 8<211> 8

<212> PRT<212> PRT

<213> 未知<213> Unknown

<220><220>

<223> /note="未知敘述：Myoma T蛋白序列"<223> /note="Unknown narrative: Myoma T protein sequence"

<400> 837 <400> 837

<210> 838<210> 838

<211> 8<211> 8

<212> PRT<212> PRT

<213> 人<213> People

<400> 838 <400> 838

<210> 839<210> 839

<211> 12<211> 12

<212> PRT<212> PRT

<213> 小鼠<213> mouse

<400> 839 <400> 839

<210> 840<210> 840

<211> 5<211> 5

<212> PRT<212> PRT

<213> 流感病毒<213> Influenza virus

<400> 840 <400> 840

<210> 841<210> 841

<211> 7<211> 7

<212> PRT<212> PRT

<213> 流感病毒<213> Influenza virus

<400> 841 <400> 841

<210> 842<210> 842

<211> 10<211> 10

<212> PRT<212> PRT

<213>δ 型肝炎病毒<213> δ hepatitis virus

<400> 842 <400> 842

<210> 843<210> 843

<211> 10<211> 10

<212> PRT<212> PRT

<213> 小鼠<213> mouse

<400> 843 <400> 843

<210> 844<210> 844

<211> 20<211> 20

<212> PRT<212> PRT

<213> 人<213> People

<400> 844 <400> 844

<210> 845<210> 845

<211> 17<211> 17

<212> PRT<212> PRT

<213> 人<213> People

<400> 845 <400> 845

<210> 846<210> 846

<211> 1423<211> 1423

<212> PRT<212> PRT

<213> 人造序列<213> Artificial sequence

<220><220>

<223> /note="人造序列敘述：合成？"<223> /note="Artificial Sequence Narrative: Synthesis?"

<400> 846 <400> 846

<210> 847<210> 847

<211> 4677<211> 4677

<212> DNA<212> DNA

<213> 人造序列<213> Artificial sequence

<220><220>

<223> /note="人造序列敘述：合成之多核？酸"<223> /note="Artificial Sequence Description: Synthetic Polynuclear Acid"

<400> 847 <400> 847

Claims (15)

一種化合物，其選自：(4-((2-((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)乙基)胺基)-4-側氧基丁基)胺甲酸苄酯；(4-((1,3-雙((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)丙-2-基)胺基)-4-側氧基丁基)胺甲酸苄酯；(4-((1,3-雙((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)-2-(((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)甲基)丙-2-基)胺基)-4-側氧基丁基)胺甲酸苄酯；N-(2-((1-(1-((1S,2R,3R,4R,5S)-4-乙醯胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基)-2,5,8,11-四氧雜十三烷-13-基)-1H-1,2,3-***-4-基)甲氧基)乙基)-4-胺基丁醯胺；4-胺基-N-{1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]丙-2-基}丁醯胺； 4-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)丁醯胺；4-胺基-N-[1,31-雙(1-{[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]甲基}-1H-1,2,3-***-4-基)-2,6,10,14,18,22,26,30-八氧雜三十一烷-16-基]丁醯胺；4-胺基-N-{1,31-雙(1-{[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]甲基}-1H-1,2,3-***-4-基)-16-[15-(1-{[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]甲基}-1H-1,2,3-***-4-基)-2,6,10,14-四氧雜十五烷-1-基]-2,6,10,14,18,22,26,30-八氧雜三十一烷-16-基}丁醯胺；N-{(1S,2R,3R,4R,5S)-1-[(己氧基)甲基]-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基}乙醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(2,5,8,11,14-五氧雜十五烷-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺；N-((1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基)-2,2,2-三氟乙醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-2,2,2-三氟乙醯胺； N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]丙醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]甲磺醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-2,2-二氟乙醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-3,3,3-三氟丙醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-N-甲基乙醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]-N-甲基甲磺醯胺；[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(羥基甲基)-6,8-二氧雜雙環[3.2.1]辛-4-基]甲基胺甲酸三級丁酯；(1S,2R,3R,4R,5S)-1-(羥基甲基)-4-(甲基胺基)-6,8-二氧雜雙環[3.2.1]辛烷-2,3-二醇氫氯化物；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(15-苯基-2,5,8,11,14-五氧雜十五烷-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺；N-[(1S,2R,3R,4R,5S)-1-(13-疊氮基-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(2,5,8,11-四氧雜十四碳-13-烯-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯 胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(2,5,8,11-四氧雜十四碳-13-炔-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺；N-[(1S,2R,3R,4R,5S)-1-(13-胺基-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺；N-[(1S,2R,3R,4R,5S)-2,3-二羥基-1-(13-羥基-2,5,8,11-四氧雜十三烷-1-基)-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺；1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-酸；乙硫羥酸S-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}酯；N-{(1S,2R,3R,4R,5S)-2,3-二羥基-1-[13-(吡啶-2-基二甲硫基)-2,5,8,11-四氧雜十三烷-1-基]-6,8-二氧雜雙環[3.2.1]辛-4-基}乙醯胺；N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-6-(吡啶-2-基二甲 硫基)己醯胺；N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-胺基丙氧基)甲基]-1H-1,2,3-***-1-基}-2,5,8,11-四氧雜十三烷-1-基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-4-基]乙醯胺氫氯酸鹽；6-疊氮基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺；N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)庚-6-烯醯胺；N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十 三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)庚-6-炔醯胺；7-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-7-側氧基庚酸(鈉鹽)；{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸苄酯；6-胺基-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)己醯胺乙酸鹽； N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己醯胺；N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-[(溴乙醯基)胺基]己醯胺；{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基}-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸4-{[(2R)-5-(胺甲醯基胺基)-2-{[(2R)-2-環戊基-2-{[6-(2,5-二側氧基-2,5-二氫-1H-吡咯-1-基)己醯基]胺基}乙醯基]胺基}戊醯基]胺基}苄酯；N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3- 二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-3,19-二側氧基-1-(吡啶-2-基二甲硫基)-7,10,13,16-四氧雜-4,20-二氮雜二十六烷-26-醯胺；N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-3,31-二側氧基-1-(吡啶-2-基二甲硫基)-7,10,13,16,19,22,25,28-八氧雜-4,32-二氮雜三十八烷-38-醯胺；N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(吡啶-2-基二甲硫基)己醯胺；{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧 雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺甲酸2-(吡啶-2-基二甲硫基)乙酯；N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-6-(4,4,5,5-四甲基-1,3,2-二氧雜環戊硼烷-2-基)己醯胺；N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}-N'-(1,3-二羥基丙-2-基)庚二醯胺；6-疊氮基-N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基 -6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺；6-(苄氧基)-N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺；乙酸(1S,2R,3R,4R,5S)-4-(乙醯胺基)-1-{13-[4-({3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-雙(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}-2-({6-[(6-羥基己醯基)胺基]己醯基}胺基)丙氧基}甲基)-1H-1,2,3-***-1-基]-2,5,8,11-四氧雜十三烷-1-基}-3-(乙醯氧基)-6,8-二氧雜雙環[3.2.1]辛-2-基酯；[6-({6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧 雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺基)-6-側氧基己基]胺甲酸苄酯；6-胺基-N-{6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}己醯胺乙酸酯；4-(苄氧基)-N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-胺基-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)丁醯胺；N-(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)-4-羥基丁醯胺；及N-(2-{[6-({6-[(1,3-雙[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]- 2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(乙醯胺基)-2,3-二羥基-6,8-二氧雜雙環[3.2.1]辛-1-基]-2,5,8,11-四氧雜十三烷-13-基}-1H-1,2,3-***-4-基)甲氧基]甲基}丙-2-基)胺基]-6-側氧基己基}胺基)-6-側氧基己基]氧基}-1,3-二噁烷-5-基)-6-(吡啶-2-基二甲硫基)己醯胺；或彼之醫藥上可接受之鹽。 a compound selected from the group consisting of: (4-((2-S(1-(1-((1S,2R,3R,4R,5S)-4-ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl)-2,5,8,11-tetraoxatridecane-13-yl)-1H-1,2,3-triazole-4 -benzyl) methoxy)ethyl)amino)-4-oxobutyl butyl) benzyl carbamate; (4-((1,3-((1S, 2R, 3R,4R,5S)-4-Ethylamino-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl)-2,5,8,11-tetra Oxatridecane-13-yl)-1H-1,2,3-triazol-4-yl)methoxy)propan-2-yl)amino)-4-oxobutylbutylamine Benzyl ester; (4-((1,3-((1S,2R,3R,4R,5S)-4-ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl)-2,5,8,11-tetraoxatridecane-13-yl)-1H-1,2,3-triazole-4- Methoxy)-2-(((1-(1-((1S,2R,3R,4R,5S)-4-ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl)-2,5,8,11-tetraoxatridecane-13-yl)-1H-1,2,3-triazol-4-yl) Benzyl oxy)methyl)propan-2-yl)amino)-4-oxobutyl butyl carbamate; N-(2-((1-(1-(1-((1S,2R,3R,4R) ,5S)-4-acetamido-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl)-2,5,8,11-tetraoxa-10- Trioxane-13-yl)-1 H-1,2,3-triazol-4-yl)methoxy)ethyl)-4-aminobutanamine; 4-amino-N-{1,3-double[(1-{1 -[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]- 2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]propan-2-yl}butanamine; 4-Amino-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6 ,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole- 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]methyl}propan-2-yl)butanamine; 4-amino-N-[1,31-bis(1-{[(1S,2R,3R,4R,5S)- 4-(acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]methyl}-1H-1,2,3-triazole- 4-yl)-2,6,10,14,18,22,26,30-octaoxatridecane-16-yl]butanamine; 4-amino-N-{1,31-double (1-{[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1- Methyl}-1}H-1,2,3-triazol-4-yl)-16-[15-(1-{[(1S,2R,3R,4R,5S)-4-(acetamide) -2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]methyl}-1H-1,2,3-triazol-4-yl)-2 ,6,10,14-tetraoxapentadecan-1-yl]-2,6,10,14,18,22,26,30-octaoxatridecane-16-yl}butanamine ;N-{(1S,2R,3R,4R,5S)-1-[(hexyloxy)methyl]-2,3-dihydroxy-6 , 8-dioxabicyclo[3.2.1]oct-4-yl}acetamidamine; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(2,5 ,8,11,14-pentaoxapentadecan-1-yl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]acetamidamine; N-((1S,2R, 3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl)-2,2,2-trifluoro Acetamine; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4 -yl]-2,2,2-trifluoroacetamide; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]-propyl Indoleamine; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4- Methylsulfonamide; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1] Oct-4-yl]-2,2-difluoroacetamide; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8 - dioxabicyclo[3.2.1]oct-4-yl]-3,3,3-trifluoropropionamide; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy 1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]-N-methylacetamide; N-[(1S,2R,3R,4R,5S )-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]-N-methylmethanesulfonamide; [(1S, 2R,3R,4R,5S)-2,3-dihydroxy-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]methylaminecarboxylic acid tert-butyl Ester; (1S, 2R, 3R, 4R, 5S)-1-(hydroxymethyl)-4-(methylamino)-6,8-dioxabicyclo[3.2.1]octane-2,3 -diol hydrochloride; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(15-phenyl-2,5,8,11,14-pentaoxa Pentadec-1-yl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]acetamide; N -[(1S,2R,3R,4R,5S)-1-(13-azido-2,5,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy- 6,8-Dioxabicyclo[3.2.1]oct-4-yl]acetamidamine; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(2, 5,8,11-tetraoxatetradecyl-13-en-1-yl)-6,8-dioxabicyclo[3.2.1]oct-4-yl]acetamidine Amine; N-[(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-(2,5,8,11-tetraoxatetradecyl-13-yn-1-yl) -6,8-Dioxabicyclo[3.2.1]oct-4-yl]acetamidamine; N-[(1S,2R,3R,4R,5S)-1-(13-amino-2,5 ,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-4-yl]acetamidamine; N-[ (1S, 2R, 3R, 4R, 5S)-2,3-dihydroxy-1-(13-hydroxy-2,5,8,11-tetraoxatridec-1-yl)-6,8- Dioxabicyclo[3.2.1]oct-4-yl]acetamidamine; 1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy- 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-acid; ethoxysulfate S-{1-[( 1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5 ,8,11-tetraoxatridecane-13-yl} ester; N-{(1S,2R,3R,4R,5S)-2,3-dihydroxy-1-[13-(pyridine-2- Dimethylthio)-2,5,8,11-tetraoxatridecyl-1-yl]-6,8-dioxabicyclo[3.2.1]oct-4-yl}acetamide; N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]-2-{[(1-{1-[(1S,2) R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)-6-(pyridine-2 -yl dimethyl Thio)hexylamine; N-[(1S,2R,3R,4R,5S)-1-(13-{4-[(3-[(1-{1-[(1S,2R,3R,4R) ,5S)-4-(acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraox Heterotridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R, 5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxa Tridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}-2-aminopropoxy)methyl]-1H-1,2, 3-triazol-1-yl}-2,5,8,11-tetraoxatridec-1-yl)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1] Oct-4-yl]acetamide hydrochloride; 6-azido-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-) (acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13 -yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-( Ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine; N-(1,3-bis[(1-{1- [(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy ]]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo [3.2.1] Oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy ]methyl}propan-2-yl)hept-6-ene decylamine; N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(B Amidino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxa-10- Trioxane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S) -4-(acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxa 13 Alkan-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hept-6-ynylamine; 7-[(1,3 - bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1 ]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2- {[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1] Oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propyl -2-yl)amino]-7-sideoxyheptanoic acid (sodium salt); {6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)) -4-(acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxa 13 Alkan-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)- 4-(acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane -13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]- Benzyl 6-oxo-oxyhexyl}amine; 6-amino-N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(acetyl) Amino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl} -1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(acetamide) -2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}- 1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)hexylamine acetate; N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6, 8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4 -yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]methyl}propan-2-yl)amino]-6-oxooxyhexyl}-6-(2,5-di- oxo-2,5-dihydro-1H-pyrrole- 1-yl)hexylamine; N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2) ,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1, 2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2, 3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2 ,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-6-[(bromoethenyl)amino]hexylamine ;{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8 -Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13- }-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethyl hydrazine) Amino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl}-2,5,8,11-tetraoxatridecane-13-yl} -1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}carbamic acid 4-{[(2R)- 5-(Aminocarboxamido)-2-{[(2R)-2-cyclopentyl-2-{[6-(2,5-di- oxo-2,5-dihydro-1H- Pyrrol-1-yl)hexyl]amino}ethyl]amino}pentanyl]amino}benzyl ester; N-(1,3-bis[(1-{1-[(1S,2R) ,3R,4R,5S)-4-(ethylammonium)-2,3- Dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3 -triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-di Hydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3- Triazol-4-yl)methoxy]methyl}propan-2-yl)-3,19-di- oxy-1-(pyridin-2-yldimethylthio)-7,10,13, 16-tetraoxa-4,20-diazahexadecane-26-decylamine; N-(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)) -4-(acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxa 13 Alkan-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)- 4-(acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane -13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)-3,31-di- oxy-1-(pyridine-2 -yldimethylthio)-7,10,13,16,19,22,25,28-octaoxa-4,32-diazatrisocane-38-decylamine; N-{6- [(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxy Heterotridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R, 5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxa Tridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-6 -(pyridin-2-yldimethylthio)hexylamine; {6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(B Amidino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxy Heterotridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R, 5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxa Tridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-amino acid 2-(pyridin-2-yldimethylthio)ethyl ester; N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-) (acetamido)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13 -yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-( Ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13- }}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexylamine; N-{6-[(1,3-bis[(1-{1-[ (1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2, 5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[( 1S, 2R, 3R, 4R, 5S) -4-(acetamido)-2,3-dihydroxy-6,8-di Oxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Methoxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}-N'-(1,3-dihydroxypropan-2-yl)heptylamine; 6-azide -N-{6-[(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-) 6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole 4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy -6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-three Zin-4-yl)methoxy]methyl}propan-2-yl)amino]-6-oxoylhexyl}hexylamine; 6-(benzyloxy)-N-{6-[(1) ,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2 .1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]- 2-{[(1-S1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2. 1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl }prop-2-yl)amino]-6-oxooxyhexyl}hexylamine; acetic acid (1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-1-{13-[ 4-({3-[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethyloxy)-6,8 -dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazole-4- Methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-bis(ethenyloxy)) -6,8-Dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-three Zin-4-yl)methoxy]methyl}-2-({6-[(6-hydroxyhexyl)) Alkyl hexyl}amino)propoxy}methyl)-1H-1,2,3-triazol-1-yl]-2,5,8,11-tetraoxatridecane-1- }}-3-(ethoxycarbonyl)-6,8-dioxabicyclo[3.2.1]oct-2-yl ester; [6-({6-[(1,3-bis[(1- {1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl ]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{ 1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxo Heterobicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl) Oxy]methyl}propan-2-yl)amino]-6-oxo-oxyhexyl}amino)-6-oxo-oxyhexyl] benzyl carbamate; 6-amino-N-{6-[ (1,3-bis[(1-S1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo) [3.2.1] Oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy ]-2-{[(1-S1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[ 3.2.1] Oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy] Methyl}prop-2-yl)amino]-6-oxooxyhexyl}hexylamine acetate; 4-(benzyloxy)-N-(1,3-bis[(1-{1- [(1S,2R,3R,4R,5S)-4-amino-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8 ,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R) ,3R,4R,5S)-4-Amino-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxy Heterotridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)butanamine; N-(1,3-double [(1-{1-[(1S,2R,3R,4R,5S)-4-(B Amino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl} -1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1-[(1S,2R,3R,4R,5S)-4-(acetamide) -2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2,5,8,11-tetraoxatridecane-13-yl}- 1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)-4-hydroxybutanamine; and N-(2-{[6-({6- [(1,3-bis[(1-{1-[(1S,2R,3R,4R,5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxa Bicyclo[3.2.1]oct-1-yl]- 2,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]-2-{[(1-{1- [(1S, 2R, 3R, 4R, 5S)-4-(ethylamino)-2,3-dihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl]-2 ,5,8,11-tetraoxatridecane-13-yl}-1H-1,2,3-triazol-4-yl)methoxy]methyl}propan-2-yl)amino] -6-oxo-oxyhexyl}amino)-6-oxo-oxyhexyl]oxy}-1,3-dioxan-5-yl)-6-(pyridin-2-yldimethylthio) Guanamine; or a pharmaceutically acceptable salt thereof. 一種式(B)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (B) Or a pharmaceutically acceptable salt thereof. 一種式(C)、(D)、(E)、(F)、(G)或(H)化合物 或 或彼之醫藥上可接受之鹽。 a compound of formula (C), (D), (E), (F), (G) or (H) or Or a pharmaceutically acceptable salt thereof. 一種式(7)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (7) Or a pharmaceutically acceptable salt thereof. 一種式(8)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (8) Or a pharmaceutically acceptable salt thereof. 一種式(9)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (9) Or a pharmaceutically acceptable salt thereof. 一種式(38A)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (38A) Or a pharmaceutically acceptable salt thereof. 一種式(41)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (41) Or a pharmaceutically acceptable salt thereof. 一種式(42)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (42) Or a pharmaceutically acceptable salt thereof. 一種式(43)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (43) Or a pharmaceutically acceptable salt thereof. 一種式(46)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (46) Or a pharmaceutically acceptable salt thereof. 一種式(48)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (48) Or a pharmaceutically acceptable salt thereof. 一種式(52)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (52) Or a pharmaceutically acceptable salt thereof. 一種式(54)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (54) Or a pharmaceutically acceptable salt thereof. 一種式(66)化合物 或彼之醫藥上可接受之鹽。 a compound of formula (66) Or a pharmaceutically acceptable salt thereof.
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